What analgesics can be used for acute or mild‑to‑moderate chronic pain in a patient who cannot take NSAIDs due to renal disease, active gastrointestinal ulcer, high cardiovascular risk, or hypersensitivity?

Alternative Analgesics When NSAIDs Are Contraindicated

Acetaminophen is the first-line analgesic for patients who cannot take NSAIDs, with a maximum dose of 3-4 grams daily, followed by tramadol or opioids for moderate-to-severe pain that does not respond to acetaminophen alone. 1

First-Line: Acetaminophen

Acetaminophen should be prescribed as the initial pharmacologic agent for all patients with NSAID contraindications. 1, 2

• Maximum dose is 4 grams daily for acute pain, but limit to 3 grams daily for chronic use due to hepatotoxicity concerns 1, 3
• Reduce dosing further in patients with liver disease 1
• Acetaminophen provides comparable pain relief to NSAIDs without gastrointestinal, renal, or cardiovascular toxicity 2
• Particularly appropriate for musculoskeletal pain and osteoarthritis 1
• Can be administered on a scheduled basis (e.g., 650-1000 mg every 4-6 hours) rather than as-needed for better chronic pain control 1

Critical caveat: When combining acetaminophen with opioid-acetaminophen products, carefully calculate total daily acetaminophen to prevent exceeding maximum dose 1

Second-Line: Tramadol

For moderate pain inadequately controlled by acetaminophen, tramadol is the preferred next step before stronger opioids. 1, 4

• Start with 50 mg every 4-6 hours as needed, maximum 400 mg daily 4
• For chronic pain, initiate with gradual titration: increase by 50 mg every 3 days to reach 200 mg/day, then continue titrating to effect 4
• Tramadol 37.5-400 mg daily (in divided doses) decreases pain and improves function in osteoarthritis over 3 months 1
• Reduce dosing interval to every 12 hours (maximum 200 mg/day) in patients with creatinine clearance <30 mL/min 4
• For patients over 75 years, do not exceed 300 mg/day 4
• For cirrhosis, use 50 mg every 12 hours 4

Third-Line: Opioid Analgesics

Opioids should be reserved for moderate-to-severe pain unresponsive to acetaminophen and tramadol, and only after careful risk assessment. 1, 2

When to Consider Opioids:

• Patients reporting moderate-to-severe pain with functional impairment despite first-line therapies 1
• Patients with severe pain and significant renal impairment where even tramadol may be problematic 2
• Cancer pain following WHO analgesic ladder progression 1

Opioid Prescribing Strategy:

• Start with the smallest effective dose combining short- and long-acting formulations 1
• For moderate pain (numerical rating scale 5-7), use low-dose strong opioids (morphine, oxycodone) or combination products with acetaminophen 1
• Hydrocodone-acetaminophen combinations are commonly used but require monitoring total acetaminophen dose 5
• Establish an opioid patient-provider agreement before initiating therapy 1
• Assess all patients for risk of misuse, diversion, and addiction prior to prescribing 1
• Implement routine monitoring including urine drug testing and pill counts 1

Important distinction: Opioids are explicitly safer than NSAIDs in patients with bleeding disorders, thrombocytopenia, renal impairment, or age >60 years 2

Condition-Specific Recommendations

For Neuropathic Pain:

• SNRI antidepressants (duloxetine) provide small-to-moderate improvements 1
• Anticonvulsants (gabapentin, pregabalin) are effective for diabetic neuropathy and postherpetic neuralgia 1
• Topical lidocaine patches or capsaicin for localized neuropathic pain 1
• Combination of morphine and gabapentin may have additive effects at lower individual doses 1

For Fibromyalgia:

• Duloxetine, milnacipran, or pregabalin are FDA-approved and recommended 1
• Tricyclic antidepressants (amitriptyline) are commonly used despite limited evidence 1

For Osteoarthritis:

• Acetaminophen scheduled dosing is first-line 1
• Duloxetine has small-to-moderate benefits, particularly in patients >65 years and knee osteoarthritis 1
• Topical NSAIDs (diclofenac) may provide localized relief with minimal systemic absorption if only superficial joints are affected 1, 3

For Temporomandibular Disorder:

• After failed nonpharmacologic interventions, consider tramadol or opioids rather than NSAIDs 1

Critical Monitoring and Safety

All patients on chronic analgesics require baseline and periodic monitoring: 1

• Blood pressure
• Renal function (BUN, creatinine)
• Liver function tests
• Complete blood count
• Stool occult blood (if any bleeding risk)

Discontinue analgesics immediately if: 1

• Creatinine doubles from baseline
• Liver enzymes exceed 3 times upper limit of normal
• New or worsening hypertension develops
• Any bleeding occurs

Common Pitfalls to Avoid

• Do not assume acetaminophen is ineffective without trying scheduled dosing at adequate doses (3-4 grams daily) 1
• Do not combine multiple acetaminophen-containing products without calculating total daily dose 1
• Do not prescribe opioids as first-line for chronic neuropathic pain—they are second- or third-line only 1
• Do not use topical NSAIDs as a "safe" alternative in patients with severe renal impairment or heart failure—systemic absorption still occurs 3
• Do not forget that tramadol has serotonergic effects and can cause serotonin syndrome when combined with SSRIs, SNRIs, or MAOIs 5