Is Maropitant Analgesic?

In a word, meh.

Maropitant is a neurokinin 1 (NK1) antagonist and this class of drugs was heavily investigated in the late 90s/early 2000s as a potential pharmacological method for pain management, especially in neuropathic pain states. But these drugs failed miserably as analgesics in human clinical trials, and, although some authors conclude differently, the data in veterinary patients is rife with issues.

Pubmed search results by year for "NK1 receptor antagonist analgesia"

The appeal of NK1 antagonists as analgesics was originally based on the neuroanatomic localization of substance P and the NK1 receptor to nociceptive sensory neurons and the dorsal horn of the spinal cord (although both substance P and the NK1 receptor are ubiquitous in mammalian tissue). In benchtop studies, NK1 antagonists attenuate hyperalgesic responses to painful stimuli by inhibiting peripheral and central sensitization. Neurokinin 1 receptor knockout mice exhibit normal baseline nociception but reduced markers of central sensitization. The combination of a plausible mechanism for analgesic effects and some favorable preclinical work led to enthusiasm for their development as marketable products.

But here are the outcomes for some of the human analgesic trials for a variety of NK1 antagonists:

Look at all those "-ve" (negative) effects!

There are a couple of positive human studies for acute dental pain, but the drug was given as an infusion and the effect was less than that of ibuprofen (Reinhardt et al. 1998) For the most part, human clinical trials have been very disappointing.

So what's out there in our species of interest?

There are some studies looking at reduction of the dose of inhalant required to stop 50% of patients from responding to a noxious stimulus with purposeful movement. That's a mouthful so we just refer to them as "MAC" studies (i.e. minimum alveolar concentration). Generally, these studies have indicated that infusion of maropitant can effect a modest reduction in MAC in dogs and cats (~15-25%) (Boscan et al. 2011; Alvillar et al. 2012; Niyom et al. 2013).

But of course, MAC reduction is not a clinical correlate of analgesia and some drugs that reduce MAC are not analgesic at all, e.g. acepromazine and midazolam.

There are also some studies that investigate pain scores, need for opioid rescue, and even the development of hyperalgesia following invasive procedures in dogs and cats (Marquez et al. 2015; Correa et al. 2019; Soares et al. 2021). A quick read through the abstracts of these articles may make you think that maropitant can be an analgesic agent but a deeper dive brings up some interesting themes.

First, in the two studies (Correa et al. 2019 and Soares et al. 2021) in which there was a reported positive effect of maropitant on analgesic outcomes, the drug was administered as an infusion at 100 mcg/kg/hr following a 1 mg/kg IV loading dose. This is of course off label and uncommonly performed. However, infusions are not terribly complicated and it wouldnt be out of reach of many practices to utilize this administration technique.

What's more problematic to me is that these studies may all be confounded by the fact that nausea and vomiting are unpleasant and create misery in and of themselves. It is a different miserable feeling from pain but it may make figuring out what is causing the animal to suffer more difficult. Humans who experience nausea and vomiting have higher pain scores and receive more opioids post operatively (Wesmiller et al. 2017) and maybe, in these animal studies, pain scores are improved and suffering - as measured by opioid requirements - is reduced in patients who receive antiemetics because the overall input of miserableness is reduced? This is all conjecture on my part but it would be interesting to do these studies with an ondansetron infusion as a comparison group.

There's just so much redundancy in this particular part of the pain pathway. Each neuron has multiple chemical messengers and several other tachykinins, including hemokinin-1, are derived from the gene that encodes substance P and can also activate NK1 receptors. There's even weird benchtop research that demonstrates that infusion of substance P into the cerebral ventricles alleviates mechanical allodynia and heat-induced hyperalgesia in an inflammatory pain model (Parenti et al. 2012) and infusion into the dorsal striatum of the brain in rats with a partially ligated sciatic nerve (a kind of horrifying neuropathic pain model) reverses mechanical hypersensitivity (Nakamura et al.) Substance P is kind of everywhere and it appears to play various roles in different tissues.

By all means, please use an antiemetic to reduce nausea and vomiting perianesthetically. Feeling sick can make a patient miserable and we should strive to reduce suffering in all forms.

We may eventually figure out specific pain states that respond well to NK1 antagonists - or NK1 antagonists in combination with another analgesic agent. In the meantime, we do know that these drugs are excellent antiemetics - and that nausea and vomiting are unpleasant experiences. Our charge as anesthetists is to minimize perianesthetic homeostatic stressors and patient suffering. So I strongly advocate for the use of antiemetics in many, if not all, veterinary patients undergoing anesthesia. But, please don't think that maropitant is a good choice as an analgesic agent in its own right. And don't think that you can drop the NSAID or opioid out of the plan in favor of a dose of maropitant!

References: Alvillar BM, Boscan P, Mama KR, et al. (2012) Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs. Vet Anaesth Analg. 39(2):201-5.

Boscan P, Monnet E, Mama K, et al. (2011). Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs Am J Vet Res. 72(12):1576-9.

Corrêa JMX, Soares PCLR, Niella RV, et al. (2019) Evaluation of the Antinociceptive Effect of Maropitant, a Neurokinin-1 Receptor Antagonist, in Cats Undergoing Ovariohysterectomy. Vet Med Int. 2019 Apr 8;2019:9352528.

Marquez M, Boscan P, Weir H, et al. (2015) Comparison of NK-1 Receptor Antagonist (Maropitant) to Morphine as a Pre-Anaesthetic Agent for Canine Ovariohysterectomy. PLoS One. 10(10):e0140734.

Nakamura Y, Fukushige R, Watanabe K, et al. (2020) Continuous infusion of substance P into rat striatum relieves mechanical hypersensitivity caused by a partial sciatic nerve ligation via activation of striatal muscarinic receptors, Behav. Brain Res. 391:112714

Niyom S, Boscan P, Twedt DC, et al. (2013) Effect of maropitant, a neurokinin-1 receptor antagonist, on the minimum alveolar concentration of sevoflurane during stimulation of the ovarian ligament in cats. Vet Anaesth Analg. 40(4):425-31.

Parenti C, Arico G, Ronsisvalle G, et al. (2012) Supraspinal injection of Substance P attenuates allodynia and hyperalgesia in a rat model of inflammatory pain. Peptides 34(2):412-8.

Reinhardt, R. (1998) Comparison of neurokinin-1 antagonist, L-745,030, to placebo, acetaminophen and ibuprofen in the dental pain model. Clin. Pharmacol. Ther. 63, 168.

Soares PCLR, Corrêa JMX, Niella RV, et al. (2021) Continuous Infusion of Ketamine and Lidocaine Either with or without Maropitant as an Adjuvant Agent for Analgesia in Female Dogs Undergoing Mastectomy. Vet Med Int. 2021 Jan 26;2021:4747301.

Wesmiller SW, Bender CM, Conley YP, et al. (2017) A Prospective Study of Nausea and Vomiting After Breast Cancer Surgery. J Perianesth Nurs. 32(3):169-176.