What are the precautions and dosage considerations when combining pregabalin and ketorolac (Non-Steroidal Anti-Inflammatory Drug, NSAID)?

Combining Pregabalin and Ketorolac: Safety and Dosing Considerations

Pregabalin and ketorolac can be safely combined for multimodal pain management, but ketorolac use must be strictly limited to 5 days maximum, with careful attention to contraindications and monitoring requirements. 1

Evidence for Combined Use

The combination of pregabalin and ketorolac has demonstrated clinical efficacy in perioperative settings:

• A prospective, double-blind randomized trial showed that an enhanced recovery pathway using preoperative pregabalin followed by perioperative ketorolac reduced morphine requirements by 40% and decreased hospital length of stay by 10% in live donor nephrectomy patients. 2
• This multimodal approach leverages pregabalin's nerve desensitization effects with ketorolac's anti-inflammatory properties to achieve opioid-sparing analgesia. 2

Critical Ketorolac Limitations

The total duration of ketorolac therapy—whether IV, IM, or oral—must never exceed 5 days due to dose-dependent adverse reactions. 1, 3

Dosing Parameters:

• Adults (17-64 years): 15-30 mg IV/IM every 6 hours, maximum 120 mg/day 3
• Elderly (≥60 years): Reduce to 15 mg IV/IM every 6 hours due to increased risk of renal failure 3
• Oral ketorolac should only be used as continuation therapy after IV/IM initiation 1

Absolute Contraindications for Ketorolac

Do not use ketorolac in patients with: 4, 3

• Active or history of peptic ulcer disease
• Aspirin/NSAID-induced asthma
• Cerebrovascular bleeding or hemorrhage
• Pregnancy
• Thrombocytopenia or concurrent anticoagulant use
• Severe renal impairment (compromised fluid status, interstitial nephritis)
• Age >60 years with significant alcohol use or hepatic dysfunction

Pregabalin Dosing Considerations

Pregabalin demonstrates predictable linear pharmacokinetics with >90% bioavailability regardless of dose: 5, 6

For Neuropathic Pain:

• Starting dose: 150 mg/day divided into 2-3 doses 7
• Maximum dose: 300-600 mg/day depending on indication 7
• Steady state achieved within 24-48 hours 5
• No hepatic metabolism or cytochrome P450 interactions 5

Key Advantages:

• Pregabalin can be administered with or without food 7
• Dose adjustment required only in renal insufficiency (creatinine clearance <60 mL/min) 7, 8
• When combined with ketorolac, pregabalin should be limited to a single preoperative dose to minimize sedation, dizziness, and peripheral edema 9

Monitoring Requirements When Using Ketorolac

Baseline assessment required: 3, 4

• Blood pressure
• BUN and creatinine
• Liver function tests
• Complete blood count
• Fecal occult blood

Discontinue ketorolac immediately if: 10, 4

• BUN or creatinine doubles
• Hypertension develops or worsens
• Liver function tests increase >3 times upper limit of normal
• Signs of gastrointestinal bleeding occur

Common Pitfalls to Avoid

Never combine ketorolac with other NSAIDs (including ibuprofen, naproxen): The National Comprehensive Cancer Network explicitly warns against concurrent NSAID use due to additive gastrointestinal bleeding, renal toxicity, and cardiovascular risks without additional analgesic benefit. 10

• If a patient has recently taken ibuprofen, wait 6-8 hours (approximately 3-4 half-lives) before administering ketorolac 10
• Consider acetaminophen or opioid analgesics as bridging therapy during this waiting period 10

Gabapentinoid dosing in combination therapy: When pregabalin is used with ketorolac for perioperative pain, limit pregabalin to a single lowest effective preoperative dose rather than continuing postoperatively to avoid synergistic sedation with other analgesics. 9

Adverse Effects Profile

Pregabalin: 9

• Blurred vision
• Cognitive effects and sedation
• Dizziness
• Weight gain
• Peripheral edema

Ketorolac: 3, 4

• Edema
• Drowsiness and dizziness
• Gastrointestinal upset and increased diaphoresis
• Highest risk of GI toxicity among NSAIDs with prolonged use 4

Clinical Algorithm for Combined Use

1. Screen for ketorolac contraindications (peptic ulcer disease, renal impairment, age >60, bleeding disorders, cardiovascular disease) 4, 3

2. Obtain baseline laboratory values (BP, BUN, creatinine, LFTs, CBC, fecal occult blood) 3

3. Administer pregabalin preoperatively (single dose 75-150 mg, 1-2 hours before surgery) 9, 2

4. Initiate ketorolac at end of surgery (15-30 mg IV, then every 6 hours) 3, 2

5. Transition to oral NSAIDs (such as ibuprofen 600 mg every 6 hours) after 24-48 hours of ketorolac 3

6. Discontinue ketorolac by day 5 regardless of pain control status 1, 3

7. Monitor for complications throughout treatment course 4, 3