Tramadol (Ultram®) versus Ketorolac (Toradol®)

Based on "Essential Pain Pharmacology"
written by Howard S. Smith, MD; Marco Pappagallo, MD

Difference between Tramadol and Ketorolac

Table 1. Comparison of tramadol vs ketorolac

Tramadol	Ketorolac
Brand names
Ultram ®	Toradol ®
Drug class
Synthetic opioid analgesic	Non-steroidal anti-inflammatory drug, non-selective COX inhibitor
Chemistry
Synthetic 4-phenylpiperidine analogue of codeine	Carboxylic acid derivative, structurally related to indomethacin
Dose formulations
• tablets • capsules, extended release • solution for injection or infusion	• tablets • solution for injection • nasal spray • ophthalmic solution
Legal status
• Rx only • Controlled substance Schedule IV	• Rx only • Not a controlled drug
FDA-approved indications
• Moderate to moderately severe pain • Moderate to moderately severe chronic pain (extended-release formulation)	• Short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level. Maximum duration of ketorolac therapy should not exceed 5 days for tablets, or 2 days for continuous daily dosing with parenteral formulations
"Off-label" uses
• Fibromyalgia • Neuropathic pain	• Athletic injuries • Injection administration into the intra-articular space • Subcutaneous administration when no other route of administration is available
Therapeutic effects
• Analgesic	• Analgesic • Anti-inflammatory (weak) • Antipyretic
Mechanism of action
• Tramadol is centrally acting analgesic • Weak µ-opioid receptor agonism • Weak norepinephrine and serotonin reuptake inhibition	• Peripherally acting analgesic • Inhibition of prostaglandin synthesis through blocking cyclooxygenase enzymes COX-1 and COX-2
Onset of action
1 hour	30-60 min
Duration of action
4-6 hours	4-6 hours
Half-life
6.3 hours	5-6 hours
Oral bioavailability
75%	80-100%
Metabolism, Elimination
• Undergoes CYP3A4- and CYP2D6 metabolism in the liver. • Excreted primarily through liver metabolism and the metabolites are eliminated primarily by the kidneys.	• Ketorolac undergoes hepatic metabolism. The metabolic products and unchanged drug are excreted in the urine.
Contraindications
• Hypersensitivity to tramadol or other opioids • Acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs	• Hypersensitivity to ketorolac • Active peptic ulcer disease • Recent gastrointestinal bleeding • Perforation • History of peptic ulcer disease or gastrointestinal bleeding. • Ketorolac should not be used as prophylactic analgesic before any major surgery • Advanced renal impairment or in patients at risk for renal failure due to volume depletion • Labor and delivery patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding • Concomitant use with other NSAIDs, probenecid, or pentoxifylline
Side effects
• Dizziness • Nausea • Constipation • Headache • Somnolence • Vomiting • Pruritus • Seizures • Risk of physical and psychological dependence	• Dyspepsia • Nausea • Headache • Fluid retention • Hyperkalemia • Elevations of ALT or AST • Gastrointestinal damage - ketorolac makes stomach lining susceptible to damage, promotes ulcers in the stomach and bleeding. • Renal injury (including renal failure, interstitial nephritis and nephrotic syndrome)
Drug interactions
• CYP2D6 and CYP3A4 inhibitors • Carbamazepine significantly increases tramadol metabolism • Quinidine • Serotonergic medications - serotonin syndrome risk	• Diuretics - reduced the natriuretic effect of furosemide and thiazides • Probenecid - concomitant use is contraindicated • ACE inhibitors, angiotensin II receptor antagonists - increased risk of renal impairment • NSAIDs - concomitant use is contraindicated because of the cumulative risk of inducing serious NSAIDs toxic effects
Pregnancy category
C	C

Ketorolac advantages over Tramadol:

Ketorolac does not bind to opioid receptors and accordingly lacks many of the side effects typically associated with opioids.
Ketorolac produces pain control comparable to opioids without respiratory depression, constipation, and tolerance.
Ketorolac is free of the potential for abuse and addiction.
Absence of any psychomotor effects and withdrawal symptoms.
Ketorolac has an opioid sparing. The drug reduces narcotic consumption by 25-45% and indirectly lowers opioid side effects such as constipation, nausea, and vomiting.

Tramadol advantages over Ketorolac:

Tramadol does not inhibit COX enzymes (inhibits prostaglandin synthesis) and accordingly lacks gastrointestinal, cardiovascular and renal toxicities typically associated with ketorolac.
Tramadol is not nephrotoxic.
Tramadol does not damage gastrointestinal tract.
Can be used in aspirin-sensitive and ulcer-prone patients.
No analgesic ceiling effect.
Unlike ketorolac does not increase surgical blood loss.
Suitable for chronic pain control.
Tramadol is available in extended-release tablets which are approved for use for an extended period of time to provide around-the-clock pain control.

Head-to-head comparative studies

Postoperative pain

There are several studies comparing the pain relieving efficacy of tramadol and ketorolac and most of them are in favor of Tramadol with regard to postoperative pain intensity10, 11, 12.

Tramadol provides better pain control for pain following surgery, and is better tolerated than ketorolac.

Ketorolac caused a higher incidence of both gastrointestinal and surgical site bleeding than did opioids.

Dental extraction pain

Oral tramadol and oral ketorolac are equally effective in relieving pain in the first 6 hours after molar extraction 9. However, postoperative tramadol has been found to be more effective than preoperative in relieving the pain, whereas the preoperative ketorolac has been found to be better than postoperative.

Oral ketorolac taken 30 min before the third molar surgery provides longer time of analgesia and less postoperative pain when compared with intramuscular tramadol administrated 30 min before surgery6.

Renal colic

Both ketorolac (30 mg intramuscular) and tramadol (1 mg/kg subcutaneous) are effective in renal colic. Both have an efficacy greater than 80% when used separately and almost 100% when used in combination. Pain relieving effect of ketorolac is achieved earlier than that of tramadol 8.

Laparoscopic procedure

Tramadol is a better analgesic compared to ketorolac for patients undergoing day care gynecologic laparoscopy 7.

References

1. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain. 1997 Nov;73(2):151-7. PubMed
2. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol. 1997 Jan;43(1):71-5. PubMed
3. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth. 1997 Nov;9(7):582-5. PubMed
4. Silvasti M, Tarkkila P, Tuominen M, Svartling N, Rosenberg PH. Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery. Eur J Anaesthesiol. 1999 Dec;16(12):834-9. PubMed
5. Smith SR, Katz JN, Collins JE, et al. Cost-Effectiveness of Tramadol and Oxycodone in the Treatment of Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2017 Feb;69(2):234-242 PubMed
6. Isiordia-Espinoza MA, Pozos-Guillen A, Martinez-Rider R, Perez-Urizar J. Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo-controlled clinical trial. Med Oral Patol Oral Cir Bucal. 2016 Sep 1;21(5):e637-43.
7. Ali A, Chohan U, Atiq F. Intravenous tramadol vs ketorolac in laparoscopic dye test. J Coll Physicians Surg Pak. 2006 Jan;16(1):3-6. PubMed
8. Nicolas Torralba JA, Rigabert Montiel M, Banon Perez V, Valdelvira Nadal P, Perez Albacete M. Intramuscular ketorolac compared to subcutaneous tramadol in the initial emergency treatment of renal colic. Arch Esp Urol. 1999 Jun;52(5):435-7. PubMed
9. Mishra H, Khan FA. A double-blind, placebo-controlled randomized comparison of pre and postoperative administration of ketorolac and tramadol for dental extraction pain. J Anaesthesiol Clin Pharmacol. 2012 Apr;28(2):221-5 PubMed
10. Shankariah M, Mishra M, Kamath RA. Tramadol versus ketorolac in the treatment of postoperative pain following maxillofacial surgery. J Maxillofac Oral Surg. 2012 Sep;11(3):264-70. PubMed
11. OlleFortuny G, Opisso Julia L, OferilRiera F, Sanchez Pallares M, Calatayud Montesa R, Cabre Roca I. Ketorolac versus tramadol: comparative study of analgesic efficacy in the postoperative pain in abdominal hysterectomy. Rev EspAnestesiolReanim. 2000 Apr;47(4):162-7.
12. Degala S, Nehal A. Comparison of intravenous tramadol versus ketorolac in the management of postoperative pain after oral and maxillofacial surgery. Oral Maxillofac Surg. 2018 May 29. PubMed