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Analgesic Drugs - Rodents and Rabbits


The Use of Analgesics in Rodents and Rabbits



Rationale


The Animal Welfare Act (AWA) defines a painful procedure as any procedure that would reasonably be expected to cause more than slight or momentary pain and/or distress in a human being to which that procedure is applied. Emory University’s Institutional Animal Care and Use Committee adopts this definition for all species and expects analgesics to be used to alleviate pain unless there is scientific justification to do otherwise.

In addition, well-established studies have shown repeatedly that effective analgesia enhances locomotion, increases appetite, and reduces the time of postoperative recovery for humans, rodents, rabbits, which are particularly sensitive to pain and inflammation, and other species. As a general rule, for maximal effectiveness, analgesics should be first administered before the animal is fully recovered from anesthesia and should be continued for the next 48-72 hours. However, as little as a single post-operative dose, in many circumstances, is sufficient to dramatically and positively influence recovery.



Mechanism of Action


Analgesics can act through several mechanisms. Centrally-acting agents, such as morphine, meperidine, codeine, nalbuphine and buprenorphine, interact with the endogenous opioid systems in the CNS. Substances that act locally at the nociceptor, such as local anesthetics, antihistamines, and alpha-2 adrenoreceptor agonists (i.e. xylazine, clonidine, metomidate), block nerve impulses. Nonsteroidal anti-inflammatory drugs (NSAID), such as aspirin, flunixin meglumine and acetaminophen, inhibit the production of the chemical mediators that activate peripheral nociceptors.




Nonsteroidal Anti-Inflammatory Drugs


NSAIDs are sufficiently potent to treat musculoskeletal, incisional, and acute, mild visceral pain. They inhibit the production of metabolic products of arachidonic acid (prostaglandins, prostacyclin) which are potent chemical mediators of inflammation that activate peripheral nociceptors. Because of different sites of action, these agents are synergistic with opioids. However, combinations of NSAIDs should not be used together as they may cause gastritis/gastric ulceration, or renal failure. Platelet inhibition is also a risk especially with agents with cyclooxygenase I activity. Carprofen (Zenecarp) has low cyclooxygenase 1 inhibitory effects and a low potential for renal or gastric toxicity (safer than flunixin). It is very effective when combined with opioids or buprenorphine and has a 24-48 hour duration of efficacy in most species.




Opioids


For the control of acute or chronic visceral pain, opioids are the most powerful and effective analgesics. Bradycardia, respiratory depression, excessive sedation, nausea, ileus and pica may be side effects. Opioid agonist-antagonists, such as buprenorphine, have minimal side effects. Opioids and opioid agonist-antagonists may increase CSF pressure and should be used with caution in craniotomy cases. In addition, the use of most of these agents is strictly controlled by the federal government requiring specialized licensure and the need to record every drop used. The use of traditional, parenterally-administered opioid analgesics such as morphine are generally impractical in rodents because of their high metabolic rates which necessitates intensive dosing schedules to maintain therapeutic blood concentrations. Buprenorphine is the most commonly used opoid in rodents due to its longer durations of action witn minimal side effects. Sustained release buprenorphine formulations are now available that release the drug over a 72-hour period after injection. The administration of NSAIDS concomitantly with opioids may allow the effective use of lower doses of opioids with fewer side effects and adequate pain management.




Recommended Analgesic Agents and Doses for Laboratory Mice
Opiods
Drug Dose (mg/kg unless noted) Route Duration Notes
Buprenorphine 0.05-0.1 SC, IP 8-12 hours In some cases, pre-operative dosing may cause peri-operative respiratory depression or prolonged anesthetic recovery. If respiratory depression is a significant concern, a half-dose may be given pre-op. When isoflurane is used, pre-emptive analgesia should be given.
Buprenorphine SR (Animalgesics) 3.25 SC 72 hours Extended release formulation. Schedule III controlled drug. Requires vet prescription. Use large needle 20-22g. Do not dilute. May cause skin reactions if drug leaks from SQ area -pinch off site after administration.
Buprenorphine SR-LAB (Zoopharm) 0.5-1.0 SC 72 hours Extended release formulation. Schedule III controlled drug. Requires vet prescription. Use large needle 20-22g. Do not dilute. May cause skin reactions if drug leaks from SQ area -pinch off site after administration. If using for the first time, start with the lower end of the dose range.
Morphine 2.5 SC, IP 2-4 hours Schedule II controlled drug. Used for severe pain
   
NSAIDS        
Drug Dose (mg/kg unless noted) Route Duration Notes
Meloxicam 5.0 SC, IP, PO 24 hours Oral suspension available
Carprofen 5.0 SC, IP 24 hours  
Ketoprofen 2.0-5.0 SC, IP 24 hours Not recommended for more than 3 days
Flunixin meglumine (Banamine) 2.5 SC, IP 12-24 hours Not commonly used
   
Local Anesthetics        
Drug Dose (mg/kg unless noted) Route Dosing interval Notes
Lidocaine Up to 4 mg/kg total dose SC/ intra-incisional Once before making incision or before suturing skin. Faster onset of action (~5 min) and duration (<1h) Dilute to 0.5%. Toxic dose is not well established in rodents. Some references give a higher toxic dose of 7 mg/kg. Can be combined with bupivicaine.
Bupivicaine Up to 2 mg/kg total dose SC/ intra-incisional Once before making incision or before suturing skin. Slower onset of action (~30min) and duration (2h) Dilute to 0.25%. Toxic dose is not well established. Some references give a higher toxic dose of 6 mg/kg. Can be combined with lidocaine.
Anesthetic creams (EMLA, xylocaine) Apply to area affected Topical application as needed Requires contact time of 20-40 min to be effective. May be useful for ear bars
* adapted with modifications from Flecknell et al. 2015. Preanesthesia, Anesthesia, Analgesia, and Euthanasia. In: Anderson, Otto, Pritchett-Corning, Wary,and Fox. (Eds.), Laboratory Animal Medicine, third ed. Elsevier/ Academic Press, New York, NY, pp. 1135-1200.
Recommended Analgesic Agents and Doses for Laboratory Rats
Opiods
Drug Dose (mg/kg unless noted) Route Duration Notes
Buprenorphine 0.01-0.05 SC, IP 8-12 hours Rat doses are reported up to 0.1, however doses > 0.05 may be associated with significant pica in some strains
Buprenorphine SR (Animalgesics) 0.65 SC 72 hours Extended release formulation. Schedule III controlled drug. Requires vet prescription. Use large needle 20-22g. Do not dilute. May cause skin reactions if drug leaks from SQ area -pinch off site after administration.
Buprenorphine SR-LAB (Zoopharm) 1.0-1.2 SC 72 hours Extended release formulation. Schedule III controlled drug. Requires vet prescription. Use large needle 20-22g. Do not dilute. May cause skin reactions if drug leaks from SQ area -pinch off site after administration. If using for the first time, start with the lower end of the dose range.
Morphine 2.5 SC, IP 2-4 hours Schedule II controlled drug. Used for severe pain
   
NSAIDS        
Drug Dose (mg/kg unless noted) Route Duration Notes
Meloxicam 1.0-2.0 SC, IP, PO, 24 hours Oral suspension available. Recommend starting with a loading dose of 2.0 mg/kg with follow-up doses at 1.0 mg/kg
Carprofen 5.0 SC, IP 24 hours  
Ketoprofen 2.0-3.0 SC, IP 24 hours Associated with fatal GI bleeding/ulceration at doses 5.0 mg/kg. Start with daily dosing at the lower end of the dose range and monitor for efficacy and side effects.
Flunixin meglumine (Banamine) 2.5 SC, IP 12-24 hours Not commonly used
   
Local Anesthetics        
Drug Dose (mg/kg unless noted) Route Dosing interval Notes
Lidocaine 1% Up to 4 mg/kg total dose SC/ intra-incisional Once before making incision or before suturing skin. Faster onset of action (~5 min) and duration (<1h) Dilute to 0.5%. Toxic dose is not well established in rodents. Some references give a higher toxic dose of 7 mg/kg. Can be combined with bupivicaine.
Bupivicaine Up to 2 mg/kg total dose SC/ intra-incisional Once before making incision or before suturing skin. Slower onset of action (~30min) and duration (2h) Dilute to 0.25%. Toxic dose is not well established. Some references give a higher toxic dose of 6 mg/kg. Can be combined with lidocaine.
Anesthetic creams (EMLA, xylocaine) Apply to area affected Topical application as needed Requires contact time of 20-40 min to be effective. May be useful for ear bars
* adapted with modifications from Flecknell et al. 2015. Preanesthesia, Anesthesia, Analgesia, and Euthanasia. In: Anderson, Otto, Pritchett-Corning, Wary,and Fox. (Eds.), Laboratory Animal Medicine, third ed. Elsevier/ Academic Press, New York, NY, pp. 1135-1200.