India's Nimesulide Dilemma: A Painkiller With Severe Side-Effects, But A Growing Market

In the Terai landscape, which constitutes the porous borders between Nepal-Uttarakhand and Nepal-Uttar Pradesh, vials containing 5-30 ml of a liquid exchange hands. The liquid is one of the most potent painkillers known to man. It is also fatal, though to an unintended recipient. 

Diclofenac, used for pain management and palliative care in bovines, has nearly wiped off the population of endemic Gyps vultures. Over 40 million raptors succumbed to kidney failure and gout in India between mid-90s and early aughts after feeding on cow carcasses that still had traces of the drug. This pushed India and Nepal to ban the drug for veterinary use in 2006.

However, diclofenac is still permitted for human use. It’s a key ingredient in topical gels such as Volini and Moov, and popular painkiller Voveran, prescribed for conditions ranging from migraines to sprains. Because it’s more potent than fellow nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, diclofenac is also used as an injectable for arthritis and musculoskeletal injuries. It’s these human-use vials, manufactured in beyond-recommended volumes by generic drugmakers, that find their way to porous borders. They’re bartered, millilitre by millilitre, between people who still administer diclofenac to animals.

“Give me a truck, and I can get a load of these from Uttarakhand, Haryana, and western Uttar Pradesh. Waha sagi maa ke alawa kuch bhi khareed sakte ho (In those parts, you can buy everything except a birth mother),” said Dr Abhijit Pawde. Pawde is the principal scientist and head of the Centre for Wildlife, Indian Veterinary Research Institute (IVRI).

His account of the underground market for diclofenac is just a prologue. The story that follows is about another NSAID, one as potent and indispensable for both humans and livestock. That drug is nimesulide. Despite decades of research about side effects in humans (notably, hepatotoxicity or liver damage) and a 2004 Delhi High Court case that catalysed a ban for paediatric use only seven years later, the nimesulide market is growing.

The Core sourced PharmaTrac data on India’s nimesulide market for human use. As of February 2024, the drug’s moving annual total (MAT) for sales has increased by nearly 15% since 2020 and is currently valued at Rs 424 crore. More than half of that is accounted for by companies that sell the fixed-dose combination (FDC) of nimesulide + paracetamol, according to PharmaTrac. Some sell for just Rs 20 a strip. Alkem Laboratories’ Sumo, Seagull Pharmaceuticals’ Nmprex-P, and Medley Pharmaceuticals’ Nimsaid-P are bestsellers in this category. Dr Reddy’s Nise — whose scope of indications ranges from menstrual cramps to joint pain — and Mankind Pharma’s Nobel are leaders in plain nimesulide formulations.

“Nise tablets are administered to humans above the age of 12 years, and not to be administered for more than 10 days. Granules for oral suspension received approval in 2022-2023 for short-term treatment,” a spokesperson for Dr Reddy’s told The Core.

 Publicly available data shows that India’s painkiller market, with a MAT of Rs 13,071 crore (as of June 2023), is primarily driven by drugs used to treat mild to moderate pain — the category nimesulide belongs to.

Another case from the Delhi High Court case in 2023 stirred India from regulatory slumber. The Drugs Technical Advisory Board (DTAB), which advises India’s drug regulator, the Central Drugs Standard Control Organisation or CDSCO, recently recommended a ban on nimesulide for veterinary use. It also directed the Indian Council of Medical Research to study nimesulide’s effect on adult humans.

Until nimesulide is banned for use in adults — a big if — Pawde reckons that vials of the stuff, much like diclofenac, will be horse-traded. After all, the drug is cheap, effective, and widely used in one of India’s fastest-growing industries: dairy.

Creatures Of Habit

India accounts for 24% of global milk production. But the world’s highest milk producer is grappling with rising costs for feed, labour, and transportation. Nimesulide, used to manage everything from mastitis (inflammation of the udder) to respiratory disease (in combination with antimicrobials,) finds favour in this context.

“Nimesulide is economical. Safer, recommended NSAIDs like meloxicam and tolfenamic acid are 40-50% more expensive than banned drugs and therefore less likely to be stocked,” Dr Rajesh Singh told The Core. Singh is a government veterinary officer in Jharkhand and editor-in-chief of Pashudhan Praharee, a bilingual monthly magazine focused on India’s livestock sector.

According to Karan Chechi, founder and research director of data platform TechSci Research, nimesulide demand has risen in conjunction with the burgeoning livestock population. This is particularly so in Uttar Pradesh, Punjab, Haryana, Gujarat, Maharashtra, and Andhra Pradesh. Major manufacturers include Sunvet Pharma, Virbac India, Zenex Animal Health, and Merck Animal Health, the veterinary division of multinational pharma giant Merck.

This, however, is much bigger than a farm flock.

If you are a pet parent or foster, chances are your dog or cat has been administered nimesulide for pain relief, though this is more likely for canines. Dogs account for 90% of India’s pet population of 33 million and counting.

“Companion animal care is likely to contribute significantly to nimesulide consumption, with the increasing trend of pet ownership. Dogs, cats, and other pets may require NSAIDs like nimesulide for conditions such as arthritis or post-surgical pain management,” Chechi said. Nimesulide is also prescribed for hip dysplasia in dogs.

If the DTAB’s recommended ban on nimesulide for veterinary use goes through, practitioners will have to scramble for alternatives such as tolfenamic acid and meloxicam that Singh referred to. Singh, however, pointed out that expecting clinics to stock safer NSAIDs would be a stretch.

It's not so much about cost as it is about systemic failure.

For perspective, not one of Delhi’s 77 government-run veterinary centres has in-patient facilities. The finding was part of a 2022 Ahimsa audit, which also revealed some centres were so defunct, that treatment was administered by sanitation workers. This is the national capital. In ‘livestock states’ where dairy farmers would cry “miracle” upon seeing an animal doctor at the block level, the situation is Kafkaesque. 

Cow vigilantism intersects with animal transport rules, which mandate that poultry should not be transported in temperatures below 15°C and above 25°C (hardly enforced, or exploited to extend to non-poultry animals too) and that owners should have a veterinary certificate to take a sick animal for a checkup (where will they get the certificate from?). Such conditions encourage nimesulide abuse.

“Because when they get to a facility, there are no reagents, instruments, or technicians. Compounders double as handlers double as veterinarians. Instead of going through all that trouble, it’s easier to buy nimesulide over the counter for a sick animal,” said veterinarian and herd management expert Dr Abdul Samad. During the 2022 lumpy skin disease outbreak that killed more than 97,000 cattle in three months, Samad issued a circular urging practitioners to avoid over-prescribing NSAIDs if initial pain management was possible in other ways.

“In my practice, I have observed an increased frequency of kidney failure in dogs [as a result of NSAID overkill],” he added. “It’s the veterinary equivalent of antibiotic overuse in humans.”

Human Nature

The quest for pain relief often begets more pain. It’s one of life’s greatest ironies that our body’s primary mode of defence — sensory neurons go berserk to warn us that something is wrong — is so unbearable, that it’s cause for pharmaceutical offence. The most popular families of painkillers, NSAIDs and opioids, have the most adverse side effects. While the former is linked to kidney and liver damage, the latter resulted in a drug-pushing addiction crisis whose estimated economic cost in the US is $634 billion (pdf). The opioid fentanyl is 50 times more potent than heroin. India is a major exporter of the opioid tramadol, which has takers in conflict-hit Sudan where fighters use it to stay awake.

It’s also ironic that nimesulide is shunned in the country of its birth. Invented by 3M Pharmaceuticals — once a division of the conglomerate best known for Post-Its — the NSAID is not approved in the US. Long prohibited in several western markets, it’s a favourite of pharma majors that market FDC painkillers in India. These FDC cocktails contain potent actives even Walter White, the main protagonist of the runaway hit TV series Breaking Bad, wouldn’t cook up in his super lab. Think diclofenac + nimesulide, nimesulide + tizanidine, nimesulide + paracetamol dispersible tablets, and other combinations available on platforms such as IndiaMART. The CDSCO banned 14 irrational FDC cocktails in 2023, only to rescind earlier this year.

Public health advocates have cried hoarse about nimesulide cocktails since the aughts. From ‘Nimesulide: The Current Controversy’, published in 2003 in the Indian Journal of Pharmacology:

“Most… drug research is funded by the pharmaceutical industry. However let not the ADR [adverse drug reaction] monitoring be dictated by the manufacturers of the drug, suspected to cause ADR. If this does not happen, truthful reporting will never occur because of the vested interests of the powerful industry lobby. More disturbing is the influence, when an organised gang of 50 private practitioners opines in favour of the dangerous drug and their opinion is considered to let the drug thrive…”

The Core reached out to five nimesulide manufacturers that are either major players in the veterinary and human-use space, or whose discontinued FDC drugs are still available in online pharmacies: Glenmark, Lupin, Zenex Animal Health, Dr Reddy's, and Merck Animal Health. At the time of publishing, only Dr Reddy’s responded to queries about the DTAB’s new directives and marketing safer alternatives.

“Given that the DTAB directive against nimesulide is for veterinary use, Nise and its operations in India are not affected by this directive. There are some studies endorsed by the Indian Medical Association, Association of Physicians in India and the European Medicines Agency on the use of nimesulide in humans, all of which find it safe in humans when used as prescribed. Should the ICMR or other agencies ever undertake further studies on this in India, we would welcome the studies as they would only serve to confirm the same,” a company spokesperson said.

We will update the copy if other pharmaceutical companies respond. Until then, this will remain a story about a proverb popularised by counterculture icon, actress, and fitness icon Jane Fonda, now co-opted by Big Pharma for Big Profits:

No pain, no gain.