Updates on avian analgesia (Proceedings)

Pain recognition

As avian practitioners, it is our ethical obligation to reduce and treat pain and stress in our avian patients. Birds are quite capable of responding to painful stimuli (nociception).  Nociception is the result of transduction, transmission, and modulation of stimuli in response to thermal, mechanical, or chemical tissue insult. Birds possess high-threshold mechanothermal, mechanochemical, mechanical, and thermal peripheral nociceptors.  The distribution of neurons in the nociceptive spinothalamic tract is similar in birds and mammals.  But more than that, birds are also capable of experience pain, which is the conscious and emotional response to noxious stimuli.  Pain can be very challenging to identify in the avian patient, even in the companion bird, and for this reason pain is often under-recognized and inadequately treated in birds.  As prey species, birds are adept at hiding pain.  In the stressful hospital setting, birds are even more likely to hide signs of pain.  Normal behaviors are altered when birds are painful.  Some signs of pain in avian patients described by owners or observed in the hospital setting include:

• Changes in social interactions
• Decreased interactions with conspecifics or human companions

• Decreased grooming of conspecifics

• Isolation from conspecifics

• Decreased vocalizations

• Guarding behavior
• Changes in posture (shifted perching position, limp, wing droop, etc.)

• Aggression towards conspecifics or human companions

• Changes in grooming behavior
• Decreased self-grooming

• Feather destructive behavior

• Self-mutilation

• General “Sick Bird Signs”
• Decreased food and water intake

• Decreased activity

• Fluffed, ruffled appearance

Treatment of pain

Treatment of pain should be directed at resolving the source of tissue injury or disease, in addition to the use of analgesic drugs and other treatments.  Signs of pain may be identified before a diagnosis is made, warranting analgesic therapy in advance of or during the collection of diagnostic information.

Regional anesthesia and analgesia

Lidocaine and bupivacaine block axonal sodium channels, interfering with action potential conduction.  Regional infiltration through line blocks and splash blocks is the most common method for administering local anesthesia and analgesia to birds.  Birds are possibly more sensitive to the adverse effects of local anesthetics, so dosages administered should not exceed the suggested dosages.

• Lidocaine 2% (20 mg/ml)
• Suggested dosage – 2 to 3 mg/kg

• Bupivacaine 0.25 to 0.50% (2.5 to 5.0 mg/ml)
• Suggested dosage – 1 to 2 mg/kg

• Comments
• Variable effectiveness in mallard ducks (Anas platyrhynchos) for brachial plexus block.

Opioids

Opioids are most often used for moderate to severe pain, such as traumatic or surgical pain.  Most opioids are rapidly absorbed and eliminated in birds.  Most opioids also have poor oral bioavailability in birds, associated with a first-pass effect in the liver, making oral administration generally ineffective. 

Avian opioid receptors

Opioids are categorized as agonists, partial agonists, mixed agonists/antagonists, or antagonists based on their ability to produce an analgesic response at a specific opioid receptor.  Regional distribution of mu, kappa, and delta opioid receptors in the forebrain and midbrain in birds are similar to mammals.  However, kappa and delta receptors are more prominent in the forebrain of pigeons (Columba livia), and 76% of receptors were kappa in one study.  Results from studies in chickens (Gallus gallus domesticus) suggest that birds may not possess distinct mu and kappa receptors, or perhaps the receptors have similar functions.  The analgesic effects of different opioid receptors in birds still have yet to be fully elucidated.

Opioid drugs

• Morphine - Pure mu-agonist
• Suggested dosage – None at this time

• Comments
• Not commonly used in birds.  Conflicting or questionable effects in birds

• Hydromorphone - Primarily a mu-agonist
• Suggested dosage – None at this time

• Comments
• At 0.60 mg/kg IM, response seen for up to 3 hours in American kestrels (Falco sparverius)

• Fentanyl - Short-acting mu-agonist
• Suggested dosage – None at this time

• Comments

• Not commonly used in birds
• No effect on thermal withdrawal threshold in cockatoos (Cacatua alba) at 0.02 mg/kg but analgesic response seen at 0.20 mg/kg.  Hyperactivity seen in some birds.

• Intravenous CRI at targeted plasma concentrations of 8, 16, and 32 ng/ml in red-tailed hawks (Buteo jamaicensis) and in Hispaniolan Amazon parrots (Amazona ventralis) was isoflurane-sparing (reduced MAC by 50% in Amazon parrots), suggesting analgesic effect

• Butorphanol - Kappa agonist, weak mu antagonist.  Mixed agonist/antagonist
• Suggested dosage
• 1 to 4 mg/kg IM q 1 to 3 hours

• 20 to 50 mcg/kg/min IV CRI (with 3 mg/kg loading dosage)

• Comments
• Most commonly used opioid in birds

• May not have thermal antinociceptive effect in kestrels at 1, 3, and 6 mg/kg IM

• Experimental long-acting liposomal-encapsulated butorphanol may extend duration of action (not yet commercially available)

• Oral bioavailability poor (<10% in Hispaniolan Amazon parrots)

• Buprenorphine - Partial mu agonist, kappa activity less well defined.  Mixed agonist/antagonist
• Suggested dosage – None at this time

• Comments
• Increased withdrawal latencies from noxious electrical stimulus in pigeons at 0.25 and 0.50 mg/kg for 2 and 5 hours, respectively.

• No analgesic effect in red-tailed hawks with orthopedic injuries at 0.25 mg/kg

• In African grey parrots (Psittacus erithacus), 0.10 mg/kg IM maintained plasma concentrations in the human analgesic range for 2 hours and increased withdrawal latencies to electrical stimulus

• Nalbuphine hydrochloride - kappa agonist, partial mu antagonist (similar to butorphanol)
• Suggested dosage – 12.5 mg/kg IM q 3 hours

• Comments
• Causes little to no sedation, no adverse effects

• Only available in injectable form (Nubain, 10 mg/ml, 20 mg/ml)

• Not a controlled substance under the DEA CSA (Controlled Substance Act)

• Nalbuphene decanoate at 33.7 mg/kg in Amazon parrots increased thermal withdrawal threshold values for up to 12 hours (not commercially available).

• Tramadol
• Opioid receptor effect –mu agonist, weak kappa and delta activity
• M1 metabolite much more potent agonist, present in birds studied to date

• Active at opiate, alpha-adrenergic, and serotonergic receptors

• Suggested dosage
• 15 mg/kg PO q 12 hours

• 30 mg/kg PO q 6 hours (Hispaniolan Amazon parrots, PD study)

• Comments
• Minimal evidence of efficacy in birds and other species

• Wide species variability

• Gabapentin (Neurontin)
• GABA analog, mode of action not completely understood, used to treat neuropathic pain in humans.  Anecdotal evidence suggests it may be of benefit in treating self-mutilation in birds.

• Suggested dosage – 10 to 80 mg/kg PO

• Comments
• Half-life at 10 mg/kg PO to Amazon parrots was 4.5 hours in one recent study.

The commercially available oral suspension of gabapentin contains xylitol and should not be used in birds.  Gabapentin should be extemporaneously compounded for each patient.

Nonsteroidal anti-inflammatory drugs

Used to relieve musculoskeletal and visceral pain.  Effective for both acute and chronic pain.  The anti-inflammatory and analgesic effects last longer than the predicted half-life, possibly due in part to strong protein binding properties. 

• Ketoprofen - Potent non-selective COX-1 inhibitor
• Suggested dosage – 2 to 5 mg/kg IM

• Comments
• Very low oral bioavailability in Japanese quail (Coturnix japonica)

• Carprofen - Weak inhibition of COX-1 and COX-2
• Suggested dosage – 1 to 4 mg/kg PO, SQ, or IM q 12 to 24 hours for less than 7 days

• Meloxicam - Selective COX-2 inhibitor
• Suggested dosage – 0.50 to 2.0 mg/kg PO q12 to 24 hours

• Comments
• Available in liquid form at 1.5 mg/ml and 0.50 mg/ml.  Injectable 5 mg/ml

• Celecoxib - Selective COX-2 inhibitor
• Suggested dosage (PDD) – 10 to 20 mg/kg PO q 24 hours for 6 to 12 weeks

Adjunctive therapies

Other therapeutic modalities have been used for analgesia with varying degrees of success, such as acupuncture, thermotherapy (cryotherapy), low level (cold) laser therapy, and therapeutic ultrasound.

Balanced (multi-modal) and preemptive analgesia

Balanced, or multi-modal, analgesia refers to the combination of analgesic drugs that act through different modalities.  The combination of two or more analgesics can produce a synergistic response.  Balanced analgesic can allow reduction of the cumulative dosages of individual drugs, reducing the likelihood of an adverse effect.  Surgical incisions and other painful procedures may induce prolonged changes in the CNS that might contribute to or prolong postoperative pain.  Therefore, preemptive analgesia, or administration of analgesics prior to a procedure that causes tissue injury, may have significant beneficial effects.

Suggested reading

Baine K, Jones MP, Cox S, Martín-Jiménez T.  Pharmacokinetics of gabapentin in Hispaniolan Amazon parrots (Amazona ventralis).  Proc Annu Conf Assoc Avian Vet, pp. 19-20, 2013.

Brenner DJ, Larsen RS, Dickinson PJ, Wack RF, Williams C, Pascoe PJ.  Development of an avian brachial plexus nerve block technique for perioperative analgesia in mallard ducks (Anas platyrhynchos).  J Avian Med Surg 24(1): 24-34, 2010.

Guzman DSM, Drazenovich TL, KuKanich B, Olsen GH, Willits NH, Paul-Murphy JR. Evaluation of thermal antinociceptive effects and pharmacokinetics after intramuscular administration of butorphanol tartrate to American kestrels (Falco sparverius). Amer J Vet Res 75(1);11-18, 2014.

Guzman DSM, Drazenovich TL, Olsen GH, Willits NH, Paul-Murphy JR. Evaluation of thermal antinociceptive effects after intramuscular administration of hydromorphone hydrochloride to American kestrels (Falco sparverius). Amer J Vet Res, 74(6); 817-822, 2013.

Guzman DSM, KuKanich B, Keuler NS, Klauer JM, Paul-Murphy JR. Antinociceptive effects of nalbuphine hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Amer J Vet Res,  72(6);736-740, 2011.

Hawkins MG, Pascoe PJ, Knych HKD, Drazenovich TL, Guzman DSM.  Effect of fentanyl citrate target-controlled-infusions on isoflurane MAC in Hispaniolan Amazon parrots (Amazona ventralis).  Proc Annu Conf Assoc Avian Vet, p. 15, 2014.

Hawkins MG, Zehnder AM, Pascoe PJ.  Cagebirds.  In: West G, Heard D, Caulkett N (eds). Zoo Animal and Wildlife Immobilization and Anesthesia, 2nd ed. Wiley Blackwell, Ames, IA, pp. 399-433, 2014.

Hawkins MG, Barron HW, Speer BL, Pollock C, Carpenter JW.  Birds.  In:  Carpenter JW (ed).  Exotic Animal Formulary, 4th ed. Elsevier, Maryland Heights, MO, 2012.               

Hoppes S, Flammer K, Hoersch K, Papich M, Paul-Murphy J. Disposition and analgesic effects of fentanyl in white cockatoos (Cacatua alba). J Avian Med Surg 17(3);124-130, 2003.

Paul-Murphy JR, Hawkins MG.  Bird-specific considerations.  In:  Gaynor JS, Muir WW (eds). Handbook of Veterinary Pain Management, 3rd ed.  Mosby, St. Louis, MO, pp.536-553, 2014.

Pavez JC, Hawkins MG, Pascoe PJ, Knych HKD, Kass PH. Effect of fentanyl target?controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red?tailed hawks (Buteo jamaicensis). Vet Anaesth Analges, 38(4);344-351, 2011.