Ketorolac

Title
Name
Institution

Abstract
The purpose of this paper is to explore the Non-Steroidal Anti-Inflammatory Drug, Toradol, which goes by the International Non-Proprietary Name of Ketorolac. It calls to attention the various studies that have been documented regarding the use of Ketorolac, its effectiveness in pain management, and the risks associated with the use of the drug. In addition, it also handles the pharmacodynamics and pharmacokinetics of Ketorolac, the bioavailability, as well as the various routes of administration. Ketorolac comparative efficacy with other NSAIDs is a major area of interest tackled here. Instances of Ketorolac diversion from its documented use will also be explored and the population to which the drug is relevant. Lastly, it addresses the different populations to which Toradol is relevant and expounds on the reasons why.
Keywords: Ketorolac, NSAIDs

Ketorolac
Introduction
The average person has encountered at least one NSAID many times in their lifetime. Some NSAIDs may be more commonly used than others, but they all have three functions; anti-inflammatory, antipyretic and analgesic. The relative degree of these functions may vary, and so do the risks associated with each. It is interesting to note that NSAIDs are subdivided into several other classes and one of which is Acetic acids, where Ketorolac is found. Compatriots in the same class include diclofenac, aceclofenac, sulindac, etodolac, among others.
For some years Ketorolac remained the only injectable NSAID in the US (Bookstaver, Miller, Rudisill, & Norris 2010).

That has changed recently and other NSAIDs have joined the bandwagon. Although it is an NSAID like any other, it has found its use mostly in postoperative pain and acute pain that is neither mild nor chronic. Since its development in 1989, different dosage forms of Ketorolac have been synthesized for various uses, like the ophthalmologic preparation in 1992 and the intranasal formulation in 2010.
Literature Review
Ketorolac shows a relative effectiveness when compared to opiate analgesics like morphine, pentazocine, and meperidine especially when used to manage moderate to severe post-operative pain (Litvak & McEvoy 1990). Indeed, it comes off as the better choice since it lacks the physical dependence, tolerance, and also the respiratory depressive effects of opiates. Since ketorolac and the opiate analgesics do not interact, they tend to be used concomittantly as adjuvants without any adverse effects (Litvak & McEvoy 1990).
In a study that involved 155 subjects, O’Hara, Fragen, Kinzer, and Pemberton, established that 90mg and 30mg of Ketorolac produced better pain scores compared to 6mg of morphine during the first 1 hour of administration. Similar pain scores were produced for the first 3 hours when the same ketorolac doses were compared with 12mg of morphine, but after the 4th hour, ketorolac maintained a better pain score. A dose-response effect was noted in the administration of Ketorolac since the 90mg produced better results than the 30mg though, like most non-narcotic analgesics, a plateau effect is observed after some dose strength is exceeded (O’Hara et al. 1987). The relative advantage of the 90mg and the 30mg ketorolac over 12mg morphine was as a result of the half-life of the NSAID.
In 2005, a black box warning was issued for the use ketorolac by the FDA and all NSAIDs after cardiac surgery. This followed two landmark studies that showed a relation between the use of valdecoxib after cardiac surgery with cardiovascular events like myocardial infarction, pulmonary embolism, and stroke (Oliveri, Jerzewski, & Kulik, 2014). As a consequence, the COX-2 inhibitor was withdrawn from the market and the rest of the NSAIDs were labeled as cardiovascular risks. Even after this, ketorolac use post-operatively in some select cardiac surgery patients has continued, since it shows some level of tolerance (Oliveri, Jerzewski, & Kulik, 2014).
Discussion
Identity and Class.
Toradol is the brand name for the Non-Steroidal Anti-Inflammatory Drug called Ketorolac. The generic name is Ketorolac tromethamine. Under the NSAIDs, it falls in the class of acetic acid derivatives with drugs like nabumetone, aceclofenac, and indomethacin. Chemically, it is a pyrrolizine carboxylic acid derivative. The pharmacological class is an analgesic of the order of NSAIDs, which do have antipyretic and anti-inflammatory activity as well.
Toradol was the first brand for ketorolac. It was manufactured by the Syntex company, which later amalgamated with the Swiss company, Hoffmann-La Roche. Since then, different dosage forms have been manufactured by different companies under different brand names. For instance, Novartis named their oral tablet Zepac, the one for Square Pharmaceuticals is Torax, while Biopharma called their brand Perilac. Besides these, there are many other manufacturers that have made their ketorolac since the expiry of the patent.
Pharmacodynamics.
Ketorolac works by inhibiting non-selectively inhibiting Cyclooxygenase enzymes that are involved in the prostaglandin synthesis cascade. The rate limiting in this cascade is the synthesis prostaglandins from arachidonic acid, and this is the exact point where NSAIDs act to bring about the anti-inflammatory effect. Peripherally, ketorolac is believed to decrease the transmission of nociceptor impulses and to lower nociceptor activating substances which ultimately results in analgesia. A complete understanding of the mode of action of NSAIDs still escapes the scientist though. The anti-inflammatory effect of Ketorolac is not as high as its analgesic properties. On the other hand, its pyretic effects are twenty-fold more than those of aspirin. In essence, it remains the most potent analgesic among all NSAIDs, but also has the highest incidence of side effects (Oliveri, Jerzewski, & Kulik, 2014). Since it is relatively inclined towards COX-1 inhibition, the inevitable effects of renal toxicity, NSAID-induced gastric ulcers, and platelet aggregation follow its use (Litvak & McEvoy 1990). COX-1 plays the housekeeping role in these organs, and interference with its synthesis is not without consequence. Although it has a dose-effect relationship, this goes up to a certain dose, after which the ceiling phenomenon occurs (Oliveri, Jerzewski, & Kulik, 2014).
Pharmacokinetics
Ketorolac can be administered intramuscularly, intravenously, orally, via the ocular route in case of topical eye problems. The S enantiomer is more analgesically active in a racemic mixture containing both [-] S and [+] R Ketorolac enantiomers. Absorption happens at almost perfect 100% even after oral administration and a steady-state plasma concentration is arrived at after a day of QID dosing. The onset of the action happens after about 30 minutes, the peak effect is achieved between 45-60 minutes and the half-life is 4-6 hours (Toradol (Hoffmann-La Roche Inc.): FDA Package Insert, Page 4″, 2018). Metabolism happens in the liver and excretion is renal with 60% unchanged (Vadivelu et al., 2015). Methotrexate, lithium, diuretics, and antihypertensives interact with ketorolac with varied results. Inhibition of renal PG synthesis contributes to the decreased natriuretic effect of thiazide diuretics while reduced clearance of methotrexate and lithium risks causing their respective toxicities. Selective Serotonin Reuptake Inhibitors like fluoxetin add to the ulceration of the GIT and so do glucocorticoids (“Toradol (Hoffmann-La Roche Inc.): FDA Package Insert, Page 4”, 2018). Digitalis toxicity ensues when digoxin is conconmittantly administered with ketorolac, and for a drug such a narrow therapeutic window like this, fatalities are inevitable.
Indications
Generally, NSAIDs are known to be used to relieve pain in conditions like gout, dysmenorrhea, and other conditions where inflammation is present like ankylosing spondylitis and rheumatoid arthritis. Ketorolac, in particular, is used in moderate to severe acute pain like the pain present after an operation and therefore it has found use post-op, and in osteoarthritis. For any pain requiring an opioid-level intervention ketorolac is the best fit. Its opioid-sparing effect enables its use as an adjuvant post-operatively (Oliveri, Jerzewski, & Kulik, 2014). Toradol has also been used in combination with phenylephrine to induce mydriasis during surgery and also in treating itchy eyes. Ketorolac medication should not be continued past 5 days. After parenteral administration, and when oral intake is needed to supplement medication, the total days should not exceed 5.
Contraindications
Numerous contraindications against NSAIDs exist and most of them apply in the use of ketorolac. As a result of inhibiting the COX-1 enzyme, platelet aggregation is interfered with and therefore ketorolac should not be used in patients who are likely to hemorrhage, as it inhibits the normal clotting function. This includes individuals with incomplete hemostasis and cerebrovascular bleeding. Those at risk of renal function impairment or those who suffer from renal diseases cannot use ketorolac and the same applies to peptic ulcer patients. These are areas where COX-1 enzymes do housekeeping (Litvak & McEvoy 1990). During the last trimester of pregnancy, taking ketorolac can lead to protracted parturition as well as the premature closure of ductus arteriosus. Moreover, individuals with known hypersensitivity to aspirin and breastfeeding mothers are also exempted from ketorolac use. The same case applies to those taking some drugs like probenecid and oxpentifylline because probenecid increases ketorolac levels while oxpentifylline causes bleeding.
Side Effects
The commonest side effects a patient experiences with ketorolac medication include drowsiness and gastrointestinal problems like nausea, constipation, diarrhea, and heartburn. Photosensitivity can also result and this presents as discoloration, sunburns, rashes, blisters, or vision alterations on exposure to sunlight. Flu-like symptoms, chills, and muscle pains should be taken seriously when they occur after Toradol medication as they are harbingers of serious allergic reactions.
Black-box Warnings.
According to the FDA, there are adverse hazards associated with ketorolac use. Top of that list is gastrointestinal risks like intestinal and stomach perforations, bleeding, and ulcers. This happens because of the curtailed secretion of prostaglandins which protect the gastrointestinal mucosa. Exposure of mucosa to gastric acid compromises its integrity and for this reason, Toradol use in geriatrics is highly discouraged. Renal papillary necrosis is another hazard that results after a reduction in renal prostaglandins. The third major boxed warning in Toradol is cardiovascular effects, which include myocardial infarction, stroke, and thrombotic events. This menace can be reduced by using the lowest effective dose of ketorolac. CVS risk cannot allow for the prophylactic use of Toradol before surgery. Known anaphylactic reactions to Toradol, hemorrhage, pregnancy, concomitant NSAID use, as well as intrathecal use are some areas that should be clearly interrogated before administering Toradol. Inclusion of intrathecal or neuraxial administration as a hazardous warning is because of the alcohol content in the Toradol brand. Maternal prostaglandins maintain the patency of the ductus arteriosus during the gestation period. When a corticosteroid or an NSAID is administered during the last trimester of the gestation period the resultant prostaglandin inhibition leads to earlier closure of this foramen intrauterine. The neonate will have oligohydrominos, unproportional hypertrophy in the right ventricle, tricuspid regurgitation, pulmonary hypertension, among others (Ndour, 2016). A patient who has exhibited severe aspirin reactions or the aspirin triad before is exempted from Toradol intake. The additive effect of using Toradol alongside other NSAIDs multiplies the adverse effects.
Diversion Rate.
Inasmuch as Toradol is not a recreational drug, it rarely gets misused or abused. Instances of illicit uses are few. Over the past two decades, however, there has been a concern of overuse of Ketorolac in the National Football League. Players use it for more than the recommended five days oblivious of the fact that any injury that leads to bleeding may have fatal implications. In most instances, it is given to players prophylactically during match days while giving it the slang name of ‘Vitamin T” (Zirm, 2016). Beyond that, abuse of Toradol is not of national importance. On the brighter side, doctors have found in it a good substitute for opiates, which are easily abused and cause dependence.
Toradol and Special Populations.
Pain relief is hard to achieve early after surgery among young men, which is the reason why Toradol has found preferential use after cardiac surgery in this patient population (Oliveri, Jerzewski, & Kulik, 2014). Ketorolac use is very relevant to the young adult men since they have a better renal function. Below the age of 16 years, Toradol is contraindicated as safety has not been established in the pediatric population. Those with an impaired renal function, cardiovascular risks, and persons under certain medication are especially advised on how to use Toradol.
The geriatric population requires a very delicate approach when administering Toradol, as they are more prone to ulceration and bleeding. The terminal plasma half-life of the drug is prolonged since the total clearance is lower compared to that of younger individuals (Vadivelu et al., 2015). Ketorolac cannot be used as a pain reliever during labor, pregnancy, or lactation. During labor, NSAIDs increase uterine hemorrhage by inhibiting uterine musculature and interfering with fetal circulation. Adverse effects of Ketorolac may be passed to a breastfeeding newborn during lactation. The relevance of not using NSAIDs during pregnancy is next to obvious. Those who find more use of this drug are people with severe pain who cannot be put on opiate analgesics for diverse reasons.
Conclusion
Save from its severe adverse effects, Toradol is the ideal pain reliever among all the NSAIDs. Its analgesic and antipyretic potencies are unmatched, therefore making it the best choice for post-operative pain management, especially for patients are at the risk of physical dependence. Physicians find a great a silver bullet in Toradol when treating severe pain with an opiate-level reliever.

References
Bookstaver, P. B., Miller, A. D., Rudisill, C. N., & Norris, L. B. (2010). Intravenous Ibuprofen: the First Injectable Product for the Treatment of Pain and Fever. Journal of Pain Research, 3, 67–79.
Litvak, K. M., & McEvoy, G. K. (1990). Ketorolac, an Injectable Nonnarcotic Analgesic. Clinical Pharmacy, 9(12), 921-935.
Ndour, D. D. (2016). Maternal use of non-steroidal antiinflammatory drugs and closure of the ductus arteriosus. The Pan African medical journal, 25, 251-251.
O’Hara, D. A., Fragen, R. J., Kinzer, M., & Pemberton, D. (1987). Ketorolac Tromethamine as Compared with Morphine Sulfate for Treatment of Postoperative Pain. Clinical Pharmacology & Therapeutics, 41(5), 556-561.
Oliveri, L., Jerzewski, K., & Kulik, A. (2014). Black Box Warning: Is Ketorolac Safe for Use After Cardiac Surgery? Journal of Cardiothoracic and Vascular Anesthesia, 28(2), 274-279.
Toradol (Hoffmann-La Roche Inc.): FDA Package Insert, Page 4. (2018). DrugInserts.com. Retrieved 27 February 2018, from https://druginserts.com/lib/rx/meds/toradol/page/4/
Vadivelu, N., Gowda, A. M., Urman, R. D., Jolly, S., Kodumudi, V., Maria, M., … & Pergolizzi, J. V. (2015). Ketorolac Tromethamine–Routes and Clinical Implications. Pain Practice, 15(2), 175-193.
Zirm, J. (2016). How Dangerous is Toradol, the NFL Pain Fix Known as ‘Vitamin T?’ STACK. Retrieved 26 February 2018, from http://www.stack.com/a/how-dangerous-is-toradol-the-nfl-pain-fix-known-as-vitamin-t