Analgesic Classification and Clinical Applications

Primary Analgesic Categories

Analgesics are divided into three main categories: nonopioid analgesics (NSAIDs and acetaminophen), adjuvant analgesics (drugs with primary non-pain indications), and opioid analgesics, each with distinct mechanisms, efficacy profiles, and safety considerations that guide their use in specific patient populations 1, 2.

Nonopioid Analgesics

Acetaminophen (Paracetamol)

Acetaminophen is the preferred first-line analgesic for mild to moderate acute pain across most patient populations, including those with liver disease, kidney disease, cardiovascular disease, gastrointestinal disorders, asthma, and older adults 3, 2.

Standard dosing: 500-1000 mg every 4-6 hours, maximum 4 grams daily in healthy adults 4
Onset of action: 15-30 minutes 4
Safety in liver disease: Safe at reduced doses of 2-3 grams daily for long-term use in cirrhotic patients; hepatotoxicity is rare when used as directed 5, 3
Advantages: No gastrointestinal, renal, or cardiovascular toxicity; no platelet inhibition 3, 2
Limitations: Least potent analgesic compared to NSAIDs and opioids; risk of acute liver failure with overdose 2

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs provide superior analgesia to acetaminophen for inflammatory and musculoskeletal pain but carry significant gastrointestinal, cardiovascular, and renal risks that limit their use in high-risk populations 4.

Mechanism and Properties

Inhibit COX-1 and COX-2 enzymes, providing anti-inflammatory, analgesic, and antipyretic effects 4
More effective than acetaminophen for moderate pain but with greater adverse event profile 2, 6

Specific NSAIDs and Dosing

Ibuprofen:

200-600 mg every 6 hours, maximum 3200 mg daily 4, 6
Onset: 15-30 minutes 4

Naproxen:

250-500 mg twice daily, maximum 1000 mg daily for long-term use 7
Equivalent OTC dosing: 440 mg (two 220 mg tablets) twice daily 7
Onset: 30 minutes 4

Diclofenac:

25-50 mg four times daily or 100 mg twice daily (extended-release) 4

Ketorolac (Toradol):

IV/IM: 15-30 mg every 6 hours, maximum 120 mg/day for adults age 17-64 8
Critical limitation: Maximum 5 days use; never combine with other NSAIDs 8

Contraindications and High-Risk Populations

Absolute contraindications:

Active gastrointestinal bleeding or peptic ulcer disease 9
Recent coronary artery bypass graft surgery 9
Advanced kidney disease (CrCl <30 mL/min) 7

Use with extreme caution or avoid:

Coronary artery disease or cardiovascular disease 4, 9
Age ≥60 years (increased GI, renal, cardiac toxicity) 6, 8
Concomitant anticoagulant or antiplatelet therapy 4, 7
Decompensated cirrhosis (risk of hepatorenal syndrome and GI hemorrhage) 5
Compromised fluid status or concurrent nephrotoxic drugs 7

Gastroprotection Strategy

Prescribe proton pump inhibitor or H2 blocker for patients with: age ≥75 years, history of peptic ulcer or GI bleeding, concurrent corticosteroids/anticoagulants/SSRIs, or significant alcohol use 7, 8

Monitoring Requirements for Long-Term NSAID Use

Every 3 months: blood pressure, BUN, creatinine, liver function tests, CBC, fecal occult blood 7
Discontinue immediately if: BUN/creatinine doubles, LFTs >3× upper limit of normal, GI bleeding occurs, or hypertension develops/worsens 7

Adjuvant Analgesics

Antidepressants

Antidepressants with dual serotonin-norepinephrine reuptake inhibition are first-line agents for neuropathic pain and fibromyalgia, with strong evidence for analgesic efficacy 4.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine (preferred first choice):

30 mg daily for one week, then 60 mg daily 6
Strong evidence for neuropathic pain, fibromyalgia, and chronic musculoskeletal pain 4
Better safety profile than tricyclics, particularly in older adults 4
NNT 6-7 for >30% pain relief in neuropathic pain 4

Other SNRIs:

Venlafaxine and milnacipran: less robust evidence but probably effective 4, 6

Tricyclic Antidepressants (TCAs)

Amitriptyline and nortriptyline:

First-line option for neuropathic pain and chronic radiculopathy 6
Strong evidence for analgesic effects 4
Major limitation: Cardiovascular side effects (hypertension, postural hypotension, arrhythmias), anticholinergic effects, and sedation limit use, especially in older adults 4
Secondary amines (desipramine, nortriptyline) preferred over tertiary amines (amitriptyline, imipramine) due to better tolerability 4

SSRIs and Other Antidepressants

Selective serotonin reuptake inhibitors (fluoxetine), bupropion, and mirtazapine lack comparable evidence of analgesic efficacy 4

Anticonvulsants

Gabapentin and pregabalin are first-line anticonvulsants for neuropathic pain (except trigeminal neuralgia) and fibromyalgia 4.

Gabapentin:

Starting dose: 100-300 mg at bedtime 6
Titrate to 900-3600 mg daily in divided doses 6
NNT 6-7 for >30% pain relief 4
Small to moderate benefits specifically for radiculopathy 6

Pregabalin:

Starting dose: 50 mg three times daily 6
Titrate to 100 mg three times daily 6
FDA-approved for fibromyalgia and neuropathic pain 4
NNT 6-9 for fibromyalgia 4

Mechanism and side effects:

Bind to calcium channels (α2-δ subunits) in brain and spinal cord, inhibiting excitatory neurotransmitter release 4
Most bothersome side effects: somnolence, dizziness, weight gain 4
Better tolerated in cirrhosis due to non-hepatic metabolism and lack of anticholinergic effects 5

Skeletal Muscle Relaxants

Approved for spasticity and acute musculoskeletal conditions 4
Cyclobenzaprine shows benefit for fibromyalgia 4
Caution: Most trials involve acute rather than chronic pain; concern for abuse and addiction potential 4

Topical Analgesics

Topical agents treat localized neuropathic or osteoarthritic pain without systemic toxicity 4.

Lidocaine patches (Lidoderm): Possibly effective for peripheral neuropathic pain 6
Capsaicin 0.075% cream: Probably effective for peripheral neuropathic pain 6
Salicylate topical preparations 4
Advantage: Minimize systemic exposure for localized pain 7

Opioid Analgesics

WHO Three-Step Ladder Approach

Step I (Mild Pain): Nonopioid analgesics ± adjuvants 4

Step II (Moderate Pain): Weak opioids (tramadol, codeine) + nonopioid ± adjuvants 4

Step III (Severe Pain): Strong opioids (morphine, oxycodone, hydromorphone, fentanyl, methadone) + nonopioid ± adjuvants 4

Weak Opioids

Tramadol:

Positioning: Second-line agent for chronic pain after NSAIDs and acetaminophen have failed 6
Starting dose: 25-50 mg every 6 hours, titrate to 200-400 mg daily 6
Provides moderate short-term pain relief (≤1 point improvement on 0-10 scale) with modest functional benefits 6
NNT: 20.7% discontinue due to therapeutic failure vs. 51.3% on placebo 6
Adverse events: Nausea, dizziness, somnolence, constipation, headache in ~49% of patients; significantly increased neurologic adverse events (OR 6.72) 6
Critical limitation: Weaker opioid receptor affinity does not guarantee safety for long-term use; dependence potential exists 6

Strong Opioids

Morphine (reference standard):

Oral: 20-40 mg starting dose, no upper limit 4
Parenteral: 5-10 mg starting dose, 3× more potent than oral 4
Adverse events: 90% experience at least one opioid-related adverse event; 34% withdraw due to side effects in long-term trials 4

Oxycodone:

1.5-2× more potent than oral morphine 4
Starting dose: 20 mg 4

Hydromorphone:

7.5× more potent than oral morphine 4
Starting dose: 8 mg 4

Fentanyl (transdermal):

4× more potent than oral morphine (calculated mg/day to µg/h) 4
Starting dose: 12 µg/h (corresponds to 30-60 mg oral morphine daily) 4
Not usually used as first opioid 4

Methadone:

4-12× more potent than oral morphine (dose-dependent: factor 4 for <90 mg, factor 8 for 90-300 mg, factor 12 for >300 mg daily morphine) 4
Starting dose: 10 mg 4
Critical caution: Marked inter-individual differences in plasma half-life and duration of action; should be initiated only by physicians with experience and expertise 4

Buprenorphine:

Oral: 75× more potent than oral morphine, starting dose 0.4 mg, maximum 4 mg daily 4
Transdermal: 4× more potent, starting dose 17.5-35 µg/h, maximum 140 µg/h 4
Previous concerns about ceiling effect and partial antagonism not substantiated by newer publications 4

Opioid Safety and Risk Management

Most serious side effects:

Overdose and death (risk increased with concurrent alcohol and CNS depressants) 10
Addiction and abuse 4, 10
Cognitive impairment, falls, respiratory depression 2

Common side effects:

Constipation (requires therapeutic laxatives; tolerance does not develop) 4, 10
Nausea, sedation, dizziness (tolerance develops) 4

Physical dependence and withdrawal:

Develops after several days to weeks of continued use 10
Never abruptly discontinue in physically dependent patients 10
Rapid tapering may lead to serious withdrawal, uncontrolled pain, suicide, or drug-seeking behavior 10
Gradual taper using patient-specific plan with multimodal pain management support 10

High-risk populations requiring caution:

Older adults (increased risk of cognitive impairment, falls, oversedation, respiratory depression) 6
History of substance abuse 10
Concurrent CNS depressants 10
Hypoalbuminemia (increased toxicity risk) 5

Prescribing safeguards:

Use immediate-release rather than controlled-release formulations in cirrhotic patients 5
Mandatory co-prescription of laxatives to prevent constipation and encephalopathy 5
Careful record-keeping of prescribing information 10
Periodic re-evaluation of therapy 10
Monitor for drug-seeking behaviors (emergency calls near office closing, refusal of appropriate examination, repeated "lost" prescriptions, "doctor shopping") 10

Special Population Considerations

Patients with Liver Disease

Acetaminophen remains safe at 2-3 grams daily for chronic use in cirrhotic patients 5, 3.

NSAIDs should be avoided due to risk of hepatorenal syndrome, renal impairment, and gastrointestinal hemorrhage 5.

Opioids have increased toxicity risk:

Use immediate-release formulations 5
Slow dose titration with careful monitoring 5
Mandatory laxative co-prescription 5

Adjuvant analgesics:

Gabapentin or pregabalin preferred for neuropathic pain (non-hepatic metabolism, no anticholinergic effects) 5
Tricyclics and anticonvulsants may be used cautiously 5

Patients with Kidney Disease

Avoid NSAIDs in moderate to severe renal impairment (CrCl <30 mL/min) 7.

Acetaminophen is safe without routine dose reduction 3.

Opioids require dose adjustment based on renal function.

Patients with Cardiovascular Disease

NSAIDs significantly increase risk of cardiac ischemic events and should be used with extreme caution or avoided 7, 9.

Acetaminophen is the preferred analgesic with no cardiovascular toxicity 3.

COX-2 selective NSAIDs should not be used when other options provide acceptable pain relief 6.

Patients with Gastrointestinal Disorders

Acetaminophen is preferred with no GI toxicity 3, 2.

If NSAIDs are necessary:

Mandatory gastroprotection with PPI or H2 blocker 7, 8
Consider topical NSAIDs for localized pain 7
Monitor for GI bleeding; discontinue immediately if occurs 7

Older Adults (≥60 Years)

Acetaminophen is first-line with no evidence supporting routine dose reduction 3, 4.

NSAIDs carry significantly increased risks of GI, renal, and cardiac toxicity 6, 8.

Duloxetine preferred over tricyclics for neuropathic pain due to better safety profile 4.

Opioids require heightened caution due to increased risk of cognitive impairment, falls, oversedation, and respiratory depression 6.

Patients with History of Substance Abuse

Avoid opioids when possible; prioritize nonopioid and adjuvant analgesics 10.

If opioids necessary:

Careful assessment and monitoring 10
Structured prescribing with frequent follow-up 10
Monitor for aberrant drug-related behaviors 6
Consider referral to pain specialist 6

Caution with skeletal muscle relaxants due to abuse potential 4.

Clinical Algorithm for Analgesic Selection

Acute Mild to Moderate Pain

First-line: Acetaminophen 500-1000 mg every 4-6 hours (max 4 g/day) 4, 3
If inadequate: Add or switch to NSAID (ibuprofen 400-600 mg every 6 hours) if no contraindications 4, 6
If still inadequate: Consider weak opioid (tramadol) or parenteral strong opioid for urgent relief 4, 6

Acute Severe Pain Requiring Urgent Relief

Parenteral strong opioids (IV or subcutaneous morphine 5-10 mg) 4
Avoid intramuscular route 4

Chronic Neuropathic Pain

First-line: Duloxetine 30 mg daily × 1 week, then 60 mg daily OR gabapentin 100-300 mg at bedtime, titrate to 900-3600 mg/day 4, 6
Alternative first-line: Pregabalin 50 mg TID, titrate to 100 mg TID 4, 6
If duloxetine/gabapentin inadequate: Tricyclic antidepressant (nortriptyline preferred over amitriptyline in older adults) 4, 6
Adjunctive topical therapy: Lidocaine patches or capsaicin cream for localized pain 6

Chronic Musculoskeletal Pain

First-line: NSAID (naproxen 250-500 mg BID) if no contraindications 6
If NSAID contraindicated: Acetaminophen up to 3 g/day 7
If inadequate: Add duloxetine 60 mg daily 6
For fibromyalgia: Pregabalin, gabapentin, or duloxetine 4
For acute exacerbations: Consider muscle relaxant (cyclobenzaprine) for short-term use 4

Cancer Pain (WHO Ladder)

Mild pain: Acetaminophen or NSAID ± adjuvants 4
Moderate pain: Add weak opioid (tramadol) 4
Severe pain: Strong opioid (morphine, oxycodone, fentanyl) + continue nonopioid ± adjuvants 4
Bone metastases: Consider radiotherapy for specific pain relief 4
Neuropathic cancer pain: Add gabapentin or tricyclic antidepressant 4

Common Pitfalls to Avoid

Never combine multiple NSAIDs (e.g., ketorolac + ibuprofen) as toxicities are additive without additional analgesic benefit 8.

Do not prescribe tramadol as first-line therapy for chronic pain; NSAIDs and acetaminophen should be tried first 6.

Do not assume tramadol is "safer" than traditional opioids for long-term use; dependence potential exists 6.

Never abruptly discontinue opioids in physically dependent patients; use gradual taper with multimodal support 10.

Do not use NSAIDs in patients with active GI bleeding, recent CABG, or severe renal impairment 9, 7.

Do not prescribe tertiary amine tricyclics (amitriptyline) as first choice in older adults; use duloxetine or secondary amine tricyclics (nortriptyline) 4.

Do not use opioids without concurrent laxatives to prevent constipation and encephalopathy 5.

Do not prescribe long-term NSAIDs without gastroprotection in high-risk patients (age ≥75, history of ulcer, anticoagulants) 7, 8.

Do not use methadone without expertise due to unpredictable pharmacokinetics 4.

Avoid NSAIDs in cirrhotic patients due to hepatorenal syndrome risk; use acetaminophen at reduced doses instead 5.

What are the different types of analgesics and their uses for managing pain in various patient populations, including those with gastrointestinal issues, kidney disease, liver disease, or a history of substance abuse?

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