Lecture 515 Hawkins

Avian Pain and Analgesia 

Presenting Author: Michelle Hawkins, VMD, Dipl ABVP (Avian),

Dept of Medicine and Epidemiology, School of Veterinary Medicine , Davis , CA

Interpretive Review and comments by Dr. Nemetz:

Pain. How do avian species perceive pain and how as veterinarians can we help relieve this pain during the treatment of medical and surgical cases. This is the question Dr. Hawkins attempted to answer.  There has been the assumption that our avian patients have a higher threshold of pain. This may be true, but one must first have a better knowledge of avian physiology to understand how they perceive pain stimuli and then must be able to recognize it.

A noxious stimulus is defined as a potentially tissue damaging stimulus. A receptor sensitive to a noxious or potentially noxious stimulus is termed a nociceptor. Pain recognition involves two processes: a peripheral process involved with detection and a central process governing the cerebral response to this information.

Peripherally 3 types of nociceptors have been identified in birds: High threshold mechano-thermal, mechanical, and thermal.

Mechano-thermal nociceptors sense mechanical stimulation and temperature.  In birds the thermal nociceptors appear to be less sensitive to cold compared to mammals, while the threshold of heat tends to be higher in avian species. This is not surprising since the body and skin temperature of birds is higher than mammals.

Peripheral sensitization occurs when tissue damage results in a drop in pH and the release of inflammatory mediators. Nociceptors become responsive when this occurs. Pain signals in birds, as in mammals, are transmitted from receptors to several areas of the midbrain and forebrain by multiple ascending spinal pathways. These similarities with mammals further support the hypothesis that birds are capable of perceiving pain.

The central nervous system (CNS) processes all noxious information. Endogenous opioid systems appear to modulate central pain processing in birds. In mammals, opioids, such as endorphin and enkephalin, act on mu (�),  kappa (к), or delta (δ) opioid receptors to inhibit pain.

Experimental evidence in birds shows that there is a relationship between activation of nociceptors and behaviors evidence of pain. Different species may also modify pain behavior with predatory species exhibiting painful behavior more readily than prey species. This is why humans, dogs, and cats perceive and express pain behavior more readily because they are all predatory species. Most pet birds fall into prey species and one must be more observant for indications of pain behavior.

In birds, signs that may indicate pain include change in temperament, restlessness, decrease in grooming (preening), reluctance to perch, lethargy, decreased appetite, constipation, dyspnea, lameness, biting or chewing at surgical incisions or wounds, or even tonic immobility to strong pain stimulus.

Once pain is recognized, how is it treated?

Three general classes of pain medication are used in avian medicine: Opioids, Non-Steroidal Anti-Inflammatory Drugs (NASIDs), and local anesthetics.

Opioids

A "opiate" is derived from morphine and codeine.  Synthetic drugs that act similar to morphine are called "opioids". They work by binding to one of the opioid receptors in the CNS. They can have agonist, antagonist, or mixed action on the receptors. The most common side effect reported is cardiac and/or respiratory depression. These drugs can be reversed with antagonists but this will also terminate the analgesia. It appears that birds have a predominate amount of Kappa-type receptors. This has been shown in pigeons and explains why birds do not appear to respond to mu agonists in the same manner as mammals.

Four opiate/opioids were discussed: Morphine, Butorphanol, Buprenorphine, and Nalbuphine.

Morphine showed little to no analgesic effects in domestic fowl.

Butorphanol (BUT) is a mixed agonist/antagonist with low activity at the mu receptor and strong agonist activity at the kappa receptor. These properties should model close to what is believed the pain receptors in birds. Studies have shown BUT to have analgesic effects, however, the effect has not been consistent or present in all species. The best effects were demonstrated in cockatoos and African grey parrots at 1-2 mg/kg.

Buprenorphine (BUP) is thought to act as a partial mu receptor agonist, but its kappa and delta receptor activities are less well defined. Effects seem to be dose related and larger doses have been shown to antagonize the drug's own agonist activity. Some reports have suggested that BUP at doses of 0.01-0.05 mg/kg may be effective in birds however at present the clinical efficacy needs further work.

Nalbuphine is believed to exert its agonist activity principally at the kappa receptor and is partially antagonistic at the mu receptor. In humans it has a lower incidence of respiratory depression and cardiovascular effects. Nalbuphine has a short elimination half-life which requires frequent administration. There are currently no reports of clinical use in birds.

Non-Steroidal Anti-Inflammatory Drugs (NASIDs)

The most famous NASID in human medicine is acetylsalicylic acid, the active ingredient in aspirin.

In the 1970s it became accepted that the most important action resulting in NSAID anti-inflammatory and analgesic effects was the inhibition of cyclo-oxygenase (COX) enzymes or the 5-lipoxygenase (LOX) enzyme. More recent studies have indicated there are two, maybe three, forms of COX enzymes (COX-1 and COX-2). It was believed that COX-1 enzymes affect normal physiological activity of the gastrointestinal tract and renal system and COX-2 enzymes affect response to pain, pyrexia, and inflammation. Therefore suppression of COX-2 held the promise for drugs to relieve pain without the gastrointestinal and renal side effects. Unfortunately, it is never that clear cut in the real world and recent work has demonstrated COX-1 and COX-2 enzymes overlap in there effects.

NASIDs are generally well absorbed after oral, subcutaneous, and intramuscular administration. All are highly protein bound and may compete with other highly protein bound drugs. Current studies in birds' show marked variation in elimination half-life related to the body weight and species of bird. This implies that studies will need to be performed separately for each bird species to determine proper drug dosing. NASIDs are mostly excreted through the kidneys.

Flunixin meglumine (FLX) is potent inhibitor of COX-1 and COX-2 and is considered a non-selective NASID. There is a lot of research in bird species with positive results, but also a number of reports with toxicity when used in birds. FLX is currently contraindicated for use in avian species.

Ketoprofen (KET)(Captopril) is a potent non-selective COX-1 inhibitor. So far it has shown mixed results in avian species with a short half-like.

Carprofen (CAR)(Rimadyl) is a weak inhibitor of both COX isoforms, but its mechanism of action has not been fully elucidated. This may explain its wide safety margin in comparison with other NASIDs. Work has been done in chickens with encouraging results but not worked out in other avian species.

Meloxicam (MEL)(Metacam) is a COX-2 selective oxicam NSAID. It has a long half-life in dogs but varies in other species. Ostriches exhibited a very rapid half-life when compared to ducks, pigeons, and chickens. A study presented at this same conference (Click here) indicates that half-life of the drug seems inversely proportional to the bird's weight, with smaller birds needing less dosing and larger birds needing perhaps increased dosing intervals.

Piroxicam is completely absorbed orally with a long half-life. It has been used in treating chronic joint disease in some species of birds, but side effects related to the gastrointestinal tract have occurred.

Celecoxib (Celebrex) is a potent, selective COX-2 inhibitor and not licensed for use in veterinary patients. It has been used (10mg/kg PO q 24hr) for the management of birds afflicted with PDD. Treatment durations of 6-12 weeks have been recommended.

Tepoxalin is a new NSAID that inhibits COX-1, COX-2, and the 5-lipoxygenase (LOX) enzyme. It has been licensed for use in dogs with osteoarthritis but no studies have been performed in any avian species.

Local Anesthetics

Local anesthetics block ion channels which prevent generation and conduction of pain impulses. Birds may be more sensitive to the toxic effects of local anesthetics than mammals. Toxicity depends largely on the balance between absorption and elimination and one study in ducks demonstrated this disparity. Toxic effects have been documented in birds at overall lower doses than in dogs. Toxic symptoms include seizures, cardiac arrest, depression, ataxia, and nystagmus.

Lidocaine has been used in birds however appropriate dosing may be difficult. Therefore commercial solutions should be diluted 1:10 with total doses not exceeding 4 mg/kg.

Benzocaine has been used topically for local analgesia during minor wound repair.

Bupivacaine is a long-acting local anesthetic. Information is scarce due to toxicity concerns.

EMLA (Eutectic Mixture of Local Anesthetic) is a mixture of 2.5% lidocaine and 2.5% prilocaine. It is used as a topical application in humans and no published studies exist in birds.

Conclusion:

Dr. Hawkins gave an exhaustive discussion of the various classes and compounds used for pain and analgesia in animals, but presently which are truly useful as well as safe in pet birds?

In the opiod group, Butorphanol (BUT) has been used the most and appears to have good, however limited ability to reduce pain in birds.

In the NSAID group, Meloxicam (MEL)(Metacam) and Celecoxib (Celebrex) have been used extensively in pet birds with positive results and minimally observed side effects. Carprofen (CAR)(Rimadyl) has also been used by several practitioners, but response has been very subjective. Ketoprofen (KET)(Captopril) has been used, but Dr. Nemetz has not used it based on its pharmokinetic principles as a COX-1 inhibitor.

In the Local Anesthetic group, Lidocaine is the only one Dr. Nemetz has used because of the unpredictable dramatic side effects of this class in avian species. It is usually used in combination with general inhalant anesthesia as an adjunct and thereby minimizing the dosing and risk of side effects.

The idea of "combination analgesia" is also possible owing to the different areas of action for each class within the body. Since opiods generally act centrally and NSAID act peripherally, smaller doses of each can be utilized to create a more balanced effect with perhaps less risk of toxicity.

There is still a great deal of work to be done in the pharmacokinetics of these various drugs specifically in our exotic avian species. However, we have come a long way in helping our avian patients deal with pain, thereby enhancing their recovery from illness and give them a more quality of life in the case of terminal disease processes.