Chapter Text

Chapter 1: Analgesics.

3.1 Pathophysiology of pain

To investigate the elimination of pain in Umamusume, first we must investigate the purpose and mechanisms of pain. Pain is a neurological sensation derived from injury or inflammation. There are many different sources of pain, however in this review we will be focusing on pathways directly related to analgesia. The precise mechanisms are unknown, however relevant clinical data has shown consistencies between human subjects and Umamusume subjects, so it is commonly believed that Umamusume share the same mechanisms as Humans. 

Pathway 1: Arachidonic Acid-Prostaglandin eicosanoid pathway

 A major signalling molecule for inflammation would be Prostaglandin. Prostaglandin is a signalling molecule produced when the immune system signals for the local tissue to undergo inflammation. The precursor molecule to Prostaglandin is the fatty acid Arachidonic Acid, which is derived from phospholipids. Arachidonic acid has many relevant eicosanoid derivatives, however our main focus will be the Cyclooxygenase-1(COX-1) and Cyclooxygenase-2(COX-2) enzymes, which convert Arachidonic acid to Prostaglandin, which is now relevant to nociception. Prostaglandin is also prevalent in gastric mucosa production, which is involved in protecting the inner lining of the stomach. 

Pathway 2: Noiciception

Nociception is the general term for pain signaling in the body. It is generally both pre-synaptic and post-synaptic in nature. The main nerve in this pathway will be the nociceptor, responsible for detecting tissue damage found in common injuries like lacerations or burns. Opioid receptors are found in these nerves, and throughout the Nociceptive pathway. The main ones however are the Mu (μ) and Kappa (κ) receptors, though there are more types of receptors that can be stimulated to depress or activate nociception. 

3.2 Analgesia & Analgesics

3.2.1 Non-Steroidal Anti-Inflamatories (NSAIDs)

NSAIDs are a common class of analgesics widely used in both human and Umamusume populations. The mechanism of action is the inhibition of COX-1 and COX-2 enzymes, which are involved in the prostaglandin eicosanoid pathway. Commonly found in tablet or capsule dosage forms, they’re first line medications alongside Paracetamol/Acetaminophen in low class analgesia. NSAIDs are also used in the management of inflammation, such as tendinitis and muscle injury. Due to the faster metabolic rates of Umamusume, the therapeutic window of NSAIDs shifts to the left, requiring bigger, or (more commonly) more frequent doses as the concentration rapidly declines over time. 

NSAIDs are split between two types, non-selective and COX2 selective inhibitors. The former is far more common and is often sold as over the counter medication. They freely bind to COX enzymes, preventing total conversion of Arachidonic Acid into Prostaglandin. The latter selectively inhibits COX-2, which has its advantages of reducing common NSAID side effects. 

The side effects of NSAIDs are often associated with chronic use. The most medically common sign of NSAID abuse will be ulceration. Prostaglandin, specifically prostaglandins found within the smooth lining of the stomach, are responsible for stimulating mucosal secretion, protecting the inner lining of the stomach. Overuse of NSAIDs (commonly more than seven days in humans, or more than 5 days in Umamusume.) can weaken the mucosal lining, causing damage to the stomach wall and causing the formation of non-infectious ulcers. 

Common NSAIDs

Non-Selective:

Aspirin

Also has anti-platelet activity connected to the eicosanoid Thromboxane. Often used as a prophylaxis medication for cardiovascular events, such as a myocardial infarction.

common dosage: 325mg, 500mg. Up to three times a day (four times in Umamusume) as needed for pain. Dosage size does not change from Human to Umamusme. 

warning: contraindicated with viral infections in young Umamusume. When given, it can cause Reye syndrome. It is recommended to instead give Paracetamol to avoid this adverse reaction. 

Ibuprophen

The most popular NSAID and is commonly found as an Over the Counter (otc) medication for the treatment of pain. 

common dosage: 400mg. Up to three times a day (four times in Umamusume) as needed for pain. Dosage size does not change from Human to Umamusume. 

Ketorolac 

Often used in analgesia in patients with Opioid sensitivity or dependence post operation. Most commonly found Intravenously. As such, dosage can vary wildly depending on the level of analgesia required. 

Mefenamic Acid

Often administered as a prescription analgesic for Menstruation pains in human women, or as pain relief during Umamusme Estrus. Important to note is Mefenamic acid and its derivatives have weak anti-inflammatory properties compared to analgesia, so is not recommended for inflammatory conditions. Also studies have not been thoroughly performed on children and Umamusume younger than 14 years of age, so efficacy and performance cannot be guaranteed. 

common dosage: 

during menstruation - 500mg loading dose, 250mg every 6 hours as needed for pain for three days. 

during Umamusume Estrus - 1500mg extended release tablet taken once with estrus inhibitors. 

COX-2 selective inhibitors:

Celecoxib

the most common COX-2 selective inhibitor, often used in the management of chronic inflammation, such as racing injuries. 

common dosage: 400mg loading dose, 200mg twice a day. 

3.2.2 Para-aminophenols

The mechanism of action of Para-aminophenols is currently not thoroughly examined. However, it is theorised that they act on Central Nervous System (CNS) Prostaglandin production, disrupting nociception centrally rather than on site like NSAIDs. The most common drug in this class is Paracetamol, also known as Acetaminophen in certain markets. Unlike NSAIDs, Para-aminophenols exhibit reduced anti-inflammatory activity, and are then not recommended for the treatment of inflammation related pain.

Paracetamol/Acetaminophen

Exhibits analgesic and anti-pyretic activity. Most common analgesic agent over the counter. First line agent for osteoarthritis. 

It is readily metabolised in the body into N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic intermediary before conjugating with glutathione. Extended use of Paracetamol is linked with Hepatic injury, and so must not be used for more than 7 days (5 days for Umamusume) in order to mitigate hepatic injury. 

Contraindicated with Acute Liver Injury, or reduced hepatic capacity. 

Common dosage: 500mg up to three times a day as needed for pain/fever. Not more than 3000mg a day for both Humans and Umamusume. 

3.2.3 Opioids 

Opioids are the first line analgesic when it comes to post-operative or traumatic injury. Opioids act on the opioid receptors, namely Kappa (κ) and Mu (μ). These cease the transmission of nociception towards the central nervous system, thus causing analgesia. 

The most significant adverse reaction is bradypnea or total respiratory depression. Common in opioid abuse. Signs of an overdose include slow/absent breathing, loss of consciousness and pinpoint pupils. 

Common Opioid agonists: 

Morphine

First Opioid drug that has been used recreationally for thousands of years. Now commonly used in the management of post-operative pain or invasive diagnostic procedures.

Common dosage forms:

Oral - As Morphine sulfate. 3 - 50mg every 4 hours, tuned to patient response. Ideally use the lowest possible dose to achieve clinical objectives. Umamusume tends to require higher doses, so it is common practice to start higher than with human patients. 

Intravenous - As Morphine sulfate. 2.5-15mg 4 hourly via slow injection. Dosing recommendations may vary based on clinical objectives.

Codine

Opioid drug commonly used in the management of severe cough. Prescription only, only used when over the counter alternatives have been exhausted. Converts into morphine in the body. 

Common dosage: 15-30mg, 3-4 times a day. Dosage should be adjusted in relation to clinical objectives. No significant dosage variation between Umamusume and Human in relation to the treatment of cough. 

Opioid Anatagonists:

Naloxone

Opioid antagonist most commonly used in opioid overdose. Reverses the effect of Opioid agonists and can precipitate withdrawal syndromes in opioid dependent individuals. 

Common dosage: For the reversal of Opioid overdose, 0.4-2mg intravenously repeated every 2-3 minutes if necessary. 

3.3 Umamusume Case study

An Umamusume was admitted into the hospital after a transfer from the clinic department of Tracen Academy.

Patient history and management

Patient is an active Umamusume in the twinkle series. During regular training, a badly misplaced step caused a fall. In the clinic staff there did a physical inspection and concluded a case of Desimitis, and requested a transfer to the nearest hospital. Here, the Umamusume was officially diagnosed with Desmitis, an inflammation of the ligaments, and was released following a prescription of Ibuprofen 400mg three times a day for seven days. The patient and her trainer filled the prescription at a nearby pharmacy and followed the regiment. 

Seven days later, the patient was readmitted to the hospital after finishing the regiment, complaining of gastric upset and tarry, black stools. An endoscopy was performed and confirmed NSAID-related non-infection peptic ulcer disease associated with the wrong medication schedule. The patient was prescribed Omeprazole (A proton pump inhibitor) and was swapped to Celecoxib 200mg twice daily. After 4 months, the inflammation has been reduced to pre-injury levels as well as the disappearance of stomach ulceration, and was then cleared to return to active training.