Dosing and selected characteristics of analgesic drugs for treatment of chronic pain in older adults

Drug	Suggested initial dose* and titration	Selected characteristics relevant to older adults
Acetaminophen (paracetamol)^¶	325 to 500 mg orally every 4 hours or 500 to 1000 mg every 6 to 8 hours (scheduled) Maximum 3 g per day, exceptions include: Maximum 2 g per day for older adults who are frail, aged ≥80, with significant organ dysfunction, or at risk for hepatotoxicity (eg, regular alcohol use or malnourished) Maximum 4 g per day may be considered for short-term use in selected older adults under medical supervision^Δ	Effective for noninflammatory pain; may decrease opioid requirements Does not alter platelet function Doses ≤2 g per day do not appear to increase risk of serious GI complications Can cause hepatoxicity at higher doses Clearance is reduced with aging To avoid overdose, warn patients about acetaminophen content in combination prescription analgesics (eg, oxycodone-acetaminophen) and OTC preparations
Opioid analgesics^◊^§: Older adults are more susceptible to opioid-induced adverse effects, including respiratory depression, hypotension, delirium, constipation, excessive sedation, and drug accumulation. Low doses should be used initially and titrated gradually to decrease risk of accumulation and overdose. The initial dose should be decreased by 25% for a 60-year-old patient and by 50% for an 80-year-old patient, from the initial dose that a 40-year-old would receive, but administered at the same intervals.
Tramadol
Immediate release^¥	Start with 25 mg orally once daily May increase daily dose by 25 to 50 mg after 3 to 7 days; give in 3 or 4 divided doses Age ≤75 years: Maximum 400 mg daily Age >75 years: Maximum 300 mg daily Renal impairment (CrCl <30 mL/min): Maximum 200 mg daily irrespective of age	Partial mu-opioid agonist with norepinephrine/serotonin reuptake; associated with analgesic dose-ceiling effect, but may be less likely to cause physical dependence Approximately one-tenth as potent as morphine; wide inter-individual variation in response Metabolized by CYP2D6 (polymorphic) to active potentially neurotoxic metabolites May cause nausea and dizziness; slowly titrate to improve tolerability in older adults May exacerbate or cause syndrome of inappropriate antidiuretic hormone (SIADH) or hyponatremia; monitor sodium level closely when starting or changing dosages Constipation and sedation less frequent than with strong opioids Renally cleared; dose adjust for renal impairment (CrCl <30 mL/min) Can interact with serotoninergic medications (eg, antidepressants and ondansetron) Avoid use in older adults at risk for seizures Due to number of potential adverse effects and relatively low potency, tramadol is not a first-line opioid choice
Extended release	Start with 100 mg orally once daily May increase daily dose by 100 mg after 5 or more days (maximum 300 mg daily) Avoid use in renal impairment (CrCl <30 mL/min)
Oxycodone
Immediate release^¥	Start with 2.5 to 5 mg orally every 4 hours as needed After 3 to 7 days, determine 24-hour dose requirement and convert to extended release	Metabolized by CYP2D6 (polymorphic) and CYP3A4 to active metabolites Blood levels increased by approximately 50% in older adults with renal insufficiency (CrCl <60 mL/min); reduce dose and titrate gradually Some opioid-tolerant patients may require every-8-hour dosing of extended-release forms for effective analgesia; a 12- to 24-hour interval is appropriate for most older adults
Extended release	Divide 24-hour dose requirement for oxycodone immediate release in 2 doses
Morphine
Immediate release	Start with 2.5 to 10 mg orally every 4 hours as needed (an oral solution is available for initial low doses; lowest tablet strength available in the United States is 15 mg) After 3 to 7 days, determine 24-hour dose requirement and convert to extended release	Best avoided in patients with kidney dysfunction, as clearance of active and potentially neurotoxic metabolites is decreased Hydromorphone or transdermal buprenorphine or fentanyl may be a better choice for older adults with renal impairment (CrCl <60 mL/min) For extended-release forms, some patients may require every-8-hour dosing for effective analgesia; a 12- to 24-hour dosing interval is appropriate for most older adults
Extended release^◊	Divide 24-hour dose requirement for immediate-release morphine in 1, 2, or 3 doses (depending on type of preparation)
Hydromorphone
Immediate release	Start with 1 to 2 mg orally every 4 hours as needed After 3 to 7 days, determine 24-hour dose requirement and covert to extended release	Metabolism to apparently inactive metabolites is an advantage over morphine in older adults with renal or hepatic insufficiency Accumulation of a neurotoxic (excitatory) metabolite may become a concern in older adults with severe renal insufficiency or ESRD
Extended release^◊	Divide 24-hour dose requirement for immediate-release hydromorphone in 1 or 2 doses (depending on type of preparation)
Transdermal fentanyl^◊	Determine 24-hour dose requirement using an immediate-release oral opioid; after 3 to 7 days, convert to an equianalgesic dose of transdermal fentanyl (refer to Lexicomp drug monograph for initial conversion) Or start with 12 mcg/hour patch every 72 hours; if ineffective after 1 week, increase to 25 mcg/hour patch	Metabolized by CYP3A4 to inactive (nontoxic) metabolites and useful in patients with renal and/or hepatic dysfunction Full effect following application of first patch is delayed by 18 to 24 hours Steady state levels may not be reached in older adults until patch is used for 6 to 9 days Avoid in opioid-naïve patients Some opioid-tolerant patients may require a 48-hour dosing interval for effective analgesia; a 72-hour dosing interval is appropriate for most older adults
Transdermal buprenorphine^◊	5 mcg/hour patch every 7 days	Partial mu agonist and weak kappa antagonist actions are associated with analgesic dose-ceiling effect but may be less likely to cause physical dependence than full agonist opioids Metabolized by CYP3A4 and glucuronidation to active metabolites Full effect following application of first patch is delayed by up to 72 hours Limited information on use in renal impairment Avoid or use with caution in opioid-naïve patients Precise role in treating older adults with painful conditions not well established
Methadone	Start with 1 mg orally, buccal, or subcutaneously every 12 to 24 hours Increase daily dose by 1 to 2 mg after 7 or more days Further increases in daily dose of 1 to 2 mg should be made no more frequently than once every 7 days	Consult with a pain specialist prior to prescribing Due to its highly variable half-life and wide inter-individual pharmacodynamics, methadone has the highest risk of accumulation and overdose during initial titration, periodic dose adjustment, and conversion from other opioids EKG should be obtained and monitored as methadone use is associated with QT interval prolongation Due to challenges inherent in safe prescribing of methadone, it is not a first-line analgesic choice For additional information, refer to the UpToDate topic reviews of treatment of chronic pain and cancer pain management with opioids
Adjuvant analgesics^§: Includes options for painful polyneuropathies, muscle spasm, and multipurpose analgesics that may decrease opioid requirements.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Duloxetine	Start with 20 to 30 mg orally per day May increase daily dose to 40 to 60 mg after 1 week Maximum 60 mg per day (CrCl ≥30 mL/min)	Effective for painful neuropathies, low back pain, fibromyalgia, and chronic musculoskeletal pain due to osteoarthritis in older adults Titrate gradually over 2 weeks or more to improve tolerability Avoid in renal impairment (CrCl <30 mL/min) or hepatic impairment
Venlafaxine (extended release)	Start with 37.5 mg orally per day May increase daily dose by 37.5 mg after 7 or more days; then may increase daily dose by 37.5 to 75 mg after 4 or more days Maximum 225 mg per day	Effective for treatment of various painful polyneuropathies but not PHN Titrate gradually over 4 weeks or more to improve tolerability Dose-related increase in diastolic blood pressure may be seen
Milnacipran	Start with 12.5 mg orally once per day (refer to Lexicomp drug monograph for titration)	Useful for treatment of various painful conditions, including fibromyalgia Dose reduction needed for renal impairment Avoid use in older adults with ESRD or significant hepatic impairment
Tricyclic antidepressants
Nortriptyline	Start with 10 mg orally at bedtime May increase daily dose by 10 mg after 7 or more days Maximum 50 mg per night	Applies to nortriptyline and desipramine: Effective for treatment of neuropathies and other painful conditions Metabolized by CYP2D6 (polymorphic) to active and inactive metabolites Dose-related anticholinergic and cardiovascular side effects may be poorly tolerated in older adults relative to SNRIs Titrate gradually over 8 weeks or more to improve tolerability Use low maintenance dose of 25 to 50 mg to decrease risk of accumulation Accumulation toxicity in older adults is less likely with nortriptyline and desipramine than other tricyclic antidepressants (eg, amitriptyline) Low doses used for treatment of painful conditions may be insufficient for treatment of depression
Desipramine	Start with 10 mg orally at bedtime May increase daily dose by 10 mg after 7 or more days Maximum 50 mg per night
Antiseizure medications
Gabapentin	Start with 100 mg orally at bedtime May increase daily dose by 100 mg after 7 or more days; give in divided doses Maximum 3600 mg per day (CrCl ≥60 mL/min)	Applies to gabapentin and pregabalin: Effective for treatment of neuropathic and other painful conditions (eg, restless legs syndrome, fibromyalgia) Highly dependent on renal function for clearance Sedation and dizziness may limit usefulness in frail older adults Use with caution with concurrent opioid use Gradual titration over weeks is suggested to improve tolerability and to decrease risk of overdose due to the delayed onset of effect Maximum maintenance dose is determined by renal function; refer to Lexicomp monograph for detail
Pregabalin	Start with 25 to 50 mg orally at bedtime May increase daily dose by 25 to 50 mg after 7 or more days; give in divided doses Maximum 300 mg per day (CrCl ≥60 mL/min)
Oral nonsteroidal antiinflammatory drugs (NSAIDs) Applies to all: Due to increased side effects in older adults, use should be limited to brief course(s) (eg, ≤1 to 2 weeks) in selected patients for painful flare-ups at lowest effective dose Avoid use of NSAIDs in older adults with renal insufficiency (CrCl <50 mL/min), GI bleeding, platelet dysfunction, reduced cardiac output, hypovolemic state, hyponatremia, hepatic impairment, or receiving antithrombotic therapy Dose- and age-associated risk of gastropathy; pharmacologic gastroprotection may be indicated even with COX-2 selective therapy (refer to UpToDate topic on prevention of NSAID-associated gastroduodenal toxicity) Can cause or worsen renal insufficiency, including age-associated decline in renal function Non-selective NSAIDs (eg, ibuprofen, naproxen) reversibly inhibit platelet function and may alter cardioprotective effects of aspirin Use with serotonin reuptake inhibitor antidepressants (eg, SSRIs, nortriptyline, venlafaxine) additively decreases platelet functioning
Naproxen sodium	220 mg orally twice per day (equivalent to 200 mg naproxen base twice per day)	May have less cardiovascular toxicity than other nonselective NSAIDs at comparable doses Naproxen sodium has faster onset than naproxen base preparations Recommended dose for older adults utilizes over-the-counter (ie, non-prescription) strength
Ibuprofen^¶	200 mg orally 3 times per day	Short half-life may be advantageous in older adults Avoid combined use with cardioprotective (low-dose) aspirin therapy
Celecoxib	100 mg orally per day	Less risk of GI toxicity relative to nonselective NSAIDs; benefit negated by low-dose aspirin, which may require concurrent gastroprotection No effect on platelet function Cardiovascular and kidney risks are dose-related and similar to nonselective NSAIDs
Diflunisal	250 mg orally 2 or 3 times per day (United States: Requires splitting a non-scored 500 mg tablet)	Applies to both nonacetylated salicylates (ie, diflunisal and salsalate): No significant effect on platelet function at doses shown Relatively lower GI bleeding risk than other nonselective NSAIDs at usual doses Relatively slow onset
Salsalate	500 mg orally 2 or 3 times per day
Topical therapies: Topical medications (eg, NSAIDs, capsaicin, and lidocaine) should be considered before oral NSAIDs for localized pain (eg, hand or knee osteoarthritis pain). They may also be used in combination with systemic analgesics to reduce doses and side effects. Refer to separate UpToDate table showing topical analgesics.
Intraarticular glucocorticoids: Refer to topic review of initial pharmacologic therapy of osteoarthritis.

INR: international normalized ratio; OTC: over-the-counter (non-prescription) medicines; CrCl: creatinine clearance; ESRD: end-stage renal disease; EKG: electrocardiogram; PHN: postherpetic neuralgia; GI: gastrointestinal; SSRI: selective serotonin reuptake inhibitor.

* Lowest starting dose shown should be considered in frail older persons with a history of sensitivity to central nervous system-active drugs, reduced cardiac output, dehydration, low body weight, or poor oral intake. Doses shown are for oral administration except where noted.

¶ Also available for parenteral use.

Δ Medical supervision means close monitoring of hepatic function and limiting exposure to other potentially hepatotoxic medications and substances (eg, alcohol), usually as an inpatient.

◊ We suggest establishing dose and effects using an immediate-release opioid preparation prior to prescribing a sustained-release opioid for opioid-naïve older patients.

§ In general, dose tapering is recommended prior to discontinuation of antiseizure medications, opioids, and antidepressants.

¥ Also available in combination preparations with acetaminophen (paracetamol).

Courtesy of Drs. Marissa Galicia-Castillo and Debra Weiner with additional data from:

McCrae JC, Morrison EE, MacIntyer IM, et al. Long-term adverse effects of paracetamol – a review. Br J Clin Pharmacol 2018; 84:2218.
Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. Lancet 2013; 382:769.
American Geriatric Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009; 57:1331.
Barkin R, Beckerman M, Blum S, et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 2010; 27:775.
van Ojik AL, Jansen PA, Brouwers JR, van Roon EN. Treatment of chronic pain in older people: evidence-based choice of strong-acting opioids. Drugs Aging 2012; 29:615.
Fitzcharles MA, Lussier D, Shir Y. Management of chronic arthritis pain in the elderly. Drugs Aging 2010; 27:471.
Nonopioid drugs for pain. Med Lett Drugs Ther 2022: 64:33.
By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2019; 67:674.

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Dosing and selected characteristics of analgesic drugs for treatment of chronic pain in older adults