Diclofenac is a widely used anti-inflammatory and antipyretic drug. Its introduction into veterinary use in South Asia was the cause of the collapse of the population of vultures of the Genus Gyps occurred between the 1990s and the 2000s. Since the discovery of its toxicity, several other Non-steroidal Anti Inflammatory drugs used in veterinary practice in many countries have been proven to be toxic to vultures and other to other birds of prey.

 

  • A group of common non-steroidal anti anti-inflammatoryinflammatory drugs (NSAIDs) used to treat livestock are known to be toxic to various scavenging raptor species, causing catastrophic declines in vulture populations of Asia.
  • The drugs are toxic to the eight species of vultures of the genus Gyps, but some are known to be toxic also for other vulture species and eagles of the genus Aquila.
  • Most licensed NSAIDs are currently untested for impacts on raptors
  • All 15 migratory old world vulture species are threatened and listed in Appendix I or II of the CMS and most are globally threatened.
  • Safe alternative drugs are available for livestock treatment and urgent action is needed to withdraw toxic NSAIDs for veterinary use and mitigate risks to raptors.

 

 

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What are Non-Steroidal Anti-Inflammatory Drugs?

NSAIDs are medicines widely used to effectively relieve pain, reduce inflammation, and reduce fever. Although NSAIDs are commonly used in human medicine, they are more recently used also in veterinary practice, mainly for the control of pain, reducing inflammation (e.g., mastitis, other swellings), and controlling fever or pyrexia.

There are at least 24 such drugs, and among the more familiar are aspirin, paracetamol, and diclofenac. Some of these drugs can represent serious threats to the populations of vultures and other raptors.

 

 

 

Facts and Figures

  • The introduction of diclofenac for veterinary use in India, Pakistan, Nepal and Bangladesh in the 1990s has resulted in the collapse of most of their vulture populations in less than 15 years (e.g., the White-rumped Vulture Gyps bengalensis declined by 99.9%).
  • Based on pre-decline population estimates, the veterinary use of NSAIDs in these countries caused millions of vulture deaths in less than two decades, before evidence that the cause of the decline was veterinary use of NSAIDs began to change exposure of vultures to toxic drugs.
  • Several NSAIDs are now scientifically proven to be toxic to the eight species of vultures of the genus Gyps. Diclofenac has been proven lethal for the
    Cinereous Vulture Aegypius monachus and suspected as toxic to eagles of the genus Aquila, the Egyptian Vulture Neophron percnopterus and Red-headed
    Vulture Sarcogyps calvus.
  • Many veterinary NSAIDs currently in use and being licensed for use have not been safety tested on scavenging raptor species.
  • Appendix I and/or II of the CMS lists 15 African-Eurasian migratory vulture species, the majority of which are globally threatened
  • The CMS Vulture Multi-species Action Plan, which aims to conserve all 15 African-Eurasian migratory vulture species, includes specific actions on NSAIDs.
  • The CMS Guidelines to Prevent the Risk of Poisoning to Migratory Birds provide clear legislative and non-legislative recommendations to prevent risk from veterinary use of NSAIDs.

 

How does NSAID toxicity affect the Raptors?

The treatment of ailing cattle with painkillers is the principal pathway by which vultures are exposed to NSAIDs.
Vultures that feed on the carcasses of cattle treated with NSAIDs a few days prior to their death, will most likely die.

Some NSAIDs are not fully metabolized by vultures and cause damage to the birds’ kidneys. This prevents uric acid, the main excretory product of birds, from being passed in the urine and its concentration in the blood increases, sometimes becoming more than ten times the normal level. Crystals of uric acid are then deposited on the bird’s organs (visceral gout) and this is a conspicuous lesion at necropsy.

It can take up to three days for a vulture to die after ingesting NSAID-contaminated flesh, by which time they will have moved some distance from the ingestion site, which can lead to uncertainty over the cause of death.

Treated cattle metabolize NSAIDs within 3-4 days of treatment and therefore do not pose a threat to vultures if they die after such a period has lapsed.
Mathematical models show that diclofenac-contaminated cattle carcasses will cause considerable decline in vulture populations even if less than 1% of carcasses have a lethal level of contamination.

 

NSAIDs in veterinary use around the world

Diclofenac was the first NSAID shown to be toxic to scavenging birds and has been banned for veterinary use in much of Asia vultures’ range. Currently, there are fully gazetted bans on the manufacture, sale and use of veterinary diclofenac in Bangladesh, Cambodia, India, Iran, Nepal, Oman and Pakistan, and other countries are considering a similar ban. 

Scientific evidence indicates that ketoprofen, nimesulide, aceclofenac, and probably flunixin are similarly toxic to vultures but, except for ketoprofen in Bangladesh, none of these NSAIDs have been banned on a national scale. Some Indian states have prohibited government supply of selected toxic NSAIDs to their veterinary services.

Some EU governments have authorized veterinary use of diclofenac and other NSAIDs. Surveys in Spain (the only country where a specific monitoring programme is in place) have shown that this toxic NSAID is present in some carcasses of domesticated animals available to foraging vultures. The NSAID flunixin has also been found in dead  Griffon vultures with post-mortem signs of kidney failure in Spain.

There is a government-sponsored programme of NSAIDs vulture safety-testing partially underway in India, with complementary work recently in South Africa. However, further NSAID safety-testing on raptors is required as all licensed NSAIDs not mentioned above are currently untested.

Safety testing experiments have established that meloxicam and tolfenamic acid are safe alternatives to diclofenac.

 

Actions under CMS

CMS Resolution 11.15 (Rev.COP13) urges Parties and Non-Parties to:

  • Ensure safety testing of existing veterinary NSAIDs;
  • Withdraw licensing of vulture-toxic NSAIDs (including diclofenac) for veterinary use; or,
  • Implement adequate risk assessment for known threats to vultures and other scavenging raptors;
  • Ensure safety testing of new veterinary NSAIDs as part of the standard protocol of research and development departments of, or financed by the pharmaceutical industry, making licensing conditional on the results of these tests; and
  • Contribute to the identification and promotion of safe alternative drugs.

NSAIDs currently known to be vulture-toxic include diclofenac, aceclofenac, nimesulide and ketoprofen, but further safety testing of other NSAIDs is likely to add to this list. The use of readily available safe alternatives in all vulture Range States is recommended.

 

Recommended decision-making process

It has also been proposed to develop a formalized approval process before market authorization is granted for all veterinary NSAIDs and seek to identify additional safe alternatives. The proces should follow the following decision making process:

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Key references

Numberous scientific papers have analysed the effect of selected  NSAIDs on vultures and other birds of prey. the list below includes the most relevant, but is by no mean a complete list. 

Chandramohan, S., Mallord, J. W., Mathesh, K., Sharma, A. K., Mahendran, K., Kesavan, M., Gupta, R.,  Chutia, K., Pawde, A., Prakash, N. V., Ravichandran, P., Saikia, D., Shringarpure, R. Timung, A., Galligan, T. H., Green, R. E. Prakash, V. M. (2022) Experimental safety testing shows that the NSAID tolfenamic acid is not toxic to Gyps vultures in India at concentrations likely to be encountered in cattle carcasses. Sci. Total Environ. 809: 152088. doi: 10.1016/j.scitotenv.2021.152088  (abstract)

Cuthbert, R., Taggart, M.A., Prakash, V., Saini, M., Swarup, D., Upreti, S., Mateo, R., Chakraborty, S.S., Deori, P. & Green, R.E. (2011) Effectiveness of Action in India to Reduce Exposure of Gyps Vultures to the Toxic Veterinary Drug Diclofenac. PLoS ONE 6(5): e19069.

Galligan, T. H., Green, R. E., Wolter, K., Taggart, M. A., Duncan, N., Mallord, J. W., Alderson, D., Li, Y., and Naidoo, V. (2022) The non-steroidal anti-inflammatory drug nimesulide kills Gyps vultures at concentrations found in the muscle of treated cattle. Sci. Total Environ. 807 (Pt 2): 150788. doi: 10.1016/j.scitotenv.2021.150788. (abstract)

Galligan, T. H., Taggart, M. A., Cuthbert, R. J., Svobodova, D., Chipangura, J., Alderson, D., Parkash, V. M. and Naidoo, V. (2016). Metabolism of aceclofenac in cattle to vulture-killing diclofenac. Conserv. Biol. 30: 1122-1127. doi: 10.1111/cobi.12711 (abstract)

Naidoo, V., Wolter, K., Cromarty, D., Diekmann, M., Duncan, N. Meharg, A. A., Taggart, M. A. Venter, L. and Cuthbert, R.  (2010) Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen. Biol Lett. 6(3): 339–341. doi: 10.1098/rsbl.2009.0818 (abstract)

Oaks, J. L., Gilbert, M., Virani, M. Z., Watson, R. T., Meteyer, C. U., Rideout, B. A., Shivaprasad, H. L., Ahmed, S., Chaudhry, M. J. I., Arshad, M., Mahmood, S., Ali, A. and Khan, A. A. (2004) Diclofenac residues as the cause of population decline of vultures in Pakistan. Nature 427: 630–633. (abstract)

Sharma, A., Saini, M., Singh, S., Prakash, V., Das, A., Bharathi Dasan, R., Cuthbert, R. (2014). Diclofenac is toxic to the Steppe Eagle Aquila nipalensis: Widening the diversity of raptors threatened by NSAID misuse in South Asia. Bird Conservation International, 24(3), 282-286. doi:10.1017/S0959270913000609 

Swan, G. E., Cuthbert, R., Quevedo, M., Green, R. E., Pain, D. J., Bartels. P., Cunningham, A. A., Duncan, N., Meharg, A. A., Oaks. L., Jones, J. M., Shultz, S., Taggart, M. A., Verdoorn, G. and Wolter, K. (2006a) Toxicity of diclofenac to Gyps vultures. Biol. Lett. 2: 279–282. (abstract)

Swan, G., Naidoo, V., Cuthbert, R., Green, R. E., Pain, D. J., Swarup, D., Prakash, V., Taggart, M., Bekker, L., Das, D., Diekmann, J., Diekmann, M., Killian, E., Meharg, A., Patra, R. C., Saini, M. and Wolter, K. (2006b) Removing the threat of diclofenac to Critically Endangered Asian Vultures. PLoS Biol. 4: 396–402.

Swarup, D., Patra, R. C., Prakash, V., Cuthbert, R., Das, D., Avari, P., Pain, D. J., Green, R. E., Sharma, A. K., Saini, M., Das, D. and Taggart, M. 2007. Safety of meloxicam to critically endangered Gyps vultures and other scavenging birds in India. Animal Conservation 10: 192–198. doi: 10.1111/j.1469-1795.2006.00086.x (abstract)

Zorrilla, I., Martinez, R., Taggart, M. A. and Richards, N. (2014). Suspected flunixin poisoning of a wild Eurasian griffon vulture from Spain. Cons. Biol. 29: 587-592. (abstract)

 

Further information on NSAIDs can be found here