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Building Pharmacists Skills in Opioid Analgesic Therapy: Appropriate Nonopioid Analgesic Administration


Pharmacologic therapy remains a cornerstone for the management of acute and chronic pain.1,2 Pharmacologic interventions may be broadly classified into 2 categories: opioid analgesics and nonopioid analgesics. The nonopioid analgesics include conventional agents such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and salicylates as well as adjuvants or coanalgesics such as certain antidepressant and antiseizure medications. Clinicians should be aware of important differences that exist between nonopioid and opioid analgesics when considering a pharmacologic option for pain management.1 One notable difference is the existence of a ceiling effect to the dose response curve with NSAID administration. This ceiling effect results in an increase in adverse effects without additional pain relief once an analgesic ceiling is reached. Additionally, conventional nonopioid analgesics are associated with beneficial antipyretic effects and do not produce physical or psychological dependence. These agents may be discontinued suddenly without a risk of withdrawal symptoms as seen with chronic opioid administration.

With the advent of the opioid crisis, the role of nonopioid analgesics in chronic pain management has been revisited. In 2016, the Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids for chronic pain recommended the utilization of nonpharmacologic and nonopioid treatments as preferred options for chronic pain management in patients not in active cancer treatment, palliative care, or end-of-life care. This recommendation was based on extensive evidence suggesting some benefit with these treatment approaches compared to chronic opioid therapy, with reduced patient harm. The guideline specifically stated that clinicians should only consider opioid therapy if the benefits on pain and function outweigh the risks to the individual patient. Additionally, the guideline recommends the combined use of opioid analgesics with nonpharmacologic therapies or nonopioid analgesics if an opioid is warranted.3

Nonopioid analgesics are a mainstay of pain control and have a significant role in evidence-based treatment for a variety of conditions. Table 1 summarizes the role of nonopioid analgesics in selected clinical practice guidelines – back pain, migraine, osteoarthritis, fibromyalgia, and diabetic neuropathy. The evidence supporting the use of nonopioid analgesics in these pain conditions varies significantly from oral NSAIDs strongly recommended for patients with knee, hip, and/or hand osteoarthritis4 to a “weak for” recommendation for amitriptyline, pregabalin, cyclobenzaprine, duloxetine, and milnacipran in the management of fibromyalgia.5 Clinicians should refer to available clinical practice guideline recommendations in order to evaluate the potential role of nonopioid analgesics in an individualized care approach.

Table 1. Role of Nonopioid Analgesics in Select Clinical Practice Guidelines.4-8
Organization Indication Recommendations
American College of Physicians4 Acute, subacute, and chronic low back pain • The majority of patients with acute or subacute low back pain improve over time regardless of treatment
• If pharmacologic treatment is required for these patients, NSAIDs or skeletal muscle relaxants are options
• In patients with chronic low back pain who have an inadequate response to nonpharmacologic interventions, NSAIDs are a first-line pharmacologic option
• Tramadol* or duloxetine are second-line options
American College of Rheumatology/Arthritis Foundation6 OA of the hand, hip, and knee • Topical NSAIDs strongly recommended for patients with knee OA; conditionally recommended for those with hand OA
• Topical capsaicin conditionally recommended for patients with knee OA and conditionally recommended against for those with hand OA
• Oral NSAIDs strongly recommended for patients with knee, hip, and/or hand OA
• Acetaminophen conditionally recommended for patients with knee, hip, and/or hand OA
• Duloxetine conditionally recommended for patients with knee, hip, and/or hand OA
American Headache Society7 Migraine • Divalproex sodium, valproate sodium, and topiramate have established efficacy in migraine prevention
• Amitriptyline and venlafaxine are probably effective in migraine prevention
• Carbamazepine is possibly effective in migraine prevention
• NSAIDs, aspirin, nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations (eg, aspirin + acetaminophen + caffeine) are effective for mild-to-moderate acute migraine attacks
European League Against Rheumatism5 Fibromyalgia • Initial management should focus on patient education and nonpharmacologic options
• If a patient has a nonresponse to the initial approach, potential patient-specific pharmacologic options (all of which were evaluated as “weak for” based on meta-analyses) include:

o Amitriptyline
o Pregabalin
o Cyclobenzaprine
o Duloxetine
o Milnacipran
American Diabetes Association8 Diabetic neuropathy • For symptomatic patients, consider pregabalin or duloxetine as an initial treatment option
• Gabapentin is another effective initial option after consideration of patients’ socioeconomic status, comorbidities, and potential for drug interactions
• Tricyclic antidepressants are also effective; however, these agents should be used with caution due to the risk of serious adverse effects
*Tramadol is discussed within the opioid analgesic module.
Abbreviations: NSAID(s), nonsteroidal anti-inflammatory drug(s); OA, osteoarthritis

Conventional Nonopioid Analgesics


Acetaminophen is an inexpensive, widely used nonopioid with both antipyretic and analgesic effects that is available in numerous over-the-counter (OTC) and prescription products.9,10 Its mechanism of action is not clearly defined; however, proposed mechanisms include central cyclo-oxygenase (COX)-3 inhibition, involvement of a serotonergic pathway, a cannabinoid-mediated mechanism, or an effect on the transient receptor potential (TRP) A1 ion channel.9,11,12 In the United States, acetaminophen is available in oral, rectal, and an intravenous formulation.13 The intravenous formulation of acetaminophen is indicated as monotherapy for the management of mild-to-moderate pain and as an adjunct to opioid analgesic therapy for the management of moderate-to-severe pain in patients ≥ 2 years of age, and for fever reduction in adult and pediatric patients.14 The recommended dosage for adult patients weighing ≥ 50 kg is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of 1000 mg. For adults weighing < 50 kg, the recommended dosage is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of 15 mg/kg. The minimum dosing interval for intravenous acetaminophen in adults is 4 hours. 

The intravenous formulation of acetaminophen is primarily for in-hospital use. The oral and rectal formulations of acetaminophen are more widely administered for fever reduction and the temporary relief of minor aches, pains, and headache.15 The usual adult analgesic dose is 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours as needed.13,15 The usual maximum total daily dose of acetaminophen, regardless of formulation, is 4 grams.13-15

In 2011, the Food and Drug Administration (FDA) required the labeling of all acetaminophen-containing prescription products to add a boxed warning regarding hepatotoxicity risk.16 Acetaminophen doses above the recommended maximum daily dose are associated with this potential serious adverse effect, which can result in acute liver failure, the need for liver transplant, and even death.15 In fact, acetaminophen-related hepatotoxicity is the leading cause of acute liver failure globally.9 Some patients may be at an increased risk for acetaminophen-related liver toxicity including the elderly, those with concurrent hepatic disease, and those who consume 3 or more alcoholic drinks daily.9,15 In these patients, clinicians should recommend further limiting acetaminophen intake. Additionally, patients should be counseled to avoid the concurrent use of multiple products containing acetaminophen as this can rapidly result in exceeding the recommended maximum daily dose and place patients at increased risk for liver damage. As part of the 2011 FDA warning, the agency also requested that drug manufacturers limit the strength of acetaminophen in prescription drug products to 325 mg per tablet, capsule, or other dosage unit in an attempt to further reduce hepatotoxicity risk.16 An overview of common medicinal products that contain acetaminophen is available at: https://liverfoundation.org/wp-content/uploads/2017/10/Common-Medicines-with-Acetaminophen-Know-Your-Dose.pdf.

The FDA also warned of rare but serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis) with acetaminophen use in 2013.17 These reactions can be fatal and may occur with the initial administration of acetaminophen or at any time during continued therapy. If such a reaction occurs, acetaminophen should be immediately discontinued, and the patient should seek urgent medical attention. Additionally, in 2015, the FDA reviewed the possible risks of analgesic medication use during pregnancy due to reports questioning their safety.18  Regarding acetaminophen, concerns arose when a cohort study concluded that maternal use during pregnancy was associated with an increased risk of attention deficit hyperactivity disorder (ADHD)-like behaviors and hyperkinetic disorders in children.19 However, the FDA concluded that the studies included in their review had potential design limitations and conflicting results. Therefore, the FDA continues to recommend that patients and clinicians continue to carefully weigh the risks and benefits of prescription and OTC pain relievers, including acetaminophen, during pregnancy.18

Drug interactions with acetaminophen are minimal; however, one of potential clinical significance is its interaction with warfarin. In patients receiving concurrent acetaminophen and warfarin, the anticoagulant effect of warfarin may be enhanced particularly with daily acetaminophen doses > 1.3 or 2 g/d for multiple consecutive days.15

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are extensively prescribed nonopioid analgesics, with 60 million prescriptions annually in the United States.9 These agents are broadly classified as nonselective or selective based upon their effects on the COX-1 and COX-2 enzymes.10 A number of nonselective NSAIDs are available (Table 2). These products reversibly inhibit the COX-1 and COX-2 enzymes, resulting in a reduction in prostaglandin precursors and subsequent antipyretic, analgesic, and anti-inflammatory effects.10,15 Celecoxib is the only selective NSAID currently available. This agent selectively inhibits the activity of the COX-2 enzyme, producing similar therapeutic effects as nonselective NSAIDs while potentially reducing gastrointestinal (GI) adverse events (eg, GI bleeding).9,15

NSAIDs are commonly administered to manage pain associated with a variety of musculoskeletal and joint disorders.9 These agents are commercially available in specific combination products and a variety of formulations including oral, rectal, ophthalmic, topical, and parenteral.15 Table 2 summarizes FDA-approved indications for oral NSAIDs. Ophthalmic NSAIDs are generally indicated for the reduction or temporary relief of pain and/or inflammation in patients who have undergone corneal refractive or cataract surgery. Topical NSAIDs include gels, solutions, and transdermal patches and are usually administered for the treatment of acute pain due to minor strains, sprains, and contusions (ie, transdermal patch) or relief of pain due to osteoarthritis of the knees and/or hands (ie, solution or gel).

Table 2. Summary of FDA-Approved Indications for Oral NSAIDs.15*
Generic Drug Name OA/RA Juvenile Arthritis Ankylosing Spondylitis Acute Pain Primary Dysmenorrhea Gout¥ Other
Non-selective NSAIDs
Diclofenac X   X X X   Migraine
Etodolac X X   X      
Fenoprofen X     X      
Flurbiprofen X            
Ibuprofen X     X X   Fever; migraine
Indomethacin X   X X   X Bursitis; tendinitis
Ketoprofen X     X X   Tendinitis
Ketorolac       X      
Meclofenamate X X X X X X Bursitis; fever; tendinitis
Mefenamic acid       X X    
Meloxicam X X          
Nabumetone X            
Naproxen X X X X X X Bursitis; tendinitis
Oxaprozin X X          
Piroxicam X            
Sulindac X   X     X Bursitis; tendinitis
Tolmetin X X          
Combination products
Diclofenac sodium/ misoprostol X            
Naproxen/ esomeprazole X X X        
Naproxen/ sumatriptan             Migraine
COX-2 selective NSAID
Celecoxib X X X X X    
Abbreviations: COX-2, cyclooxygenase-2; FDA, Food and Drug Administration; NSAID(s), nonsteroidal anti-inflammatory drug(s); OA, osteoarthritis; RA, rheumatoid arthritis.

*Specific formulations (eg, immediate vs extended release) may have approval for certain indications. Please refer to the package labeling of the individual oral NSAID for further information.

¥Indication may be specific for acute gout or gouty arthritis depending upon NSAID.

Table 3 discusses the usual adult dosage regimens for the oral NSAIDs for pain relief. Most oral NSAID products share a contraindication for use in patients with a history of asthma, urticaria, or other allergic-type reaction after being administered aspirin or other NSAIDs and during the perioperative period in patients undergoing coronary artery bypass graft surgery.15 Of note, celecoxib should not be administered to patients with a sulfonamide hypersensitivity.20 Ketorolac has specific contraindications including an active or history of peptic ulcer disease, recent or history of GI bleeding or perforation, advanced renal disease or risk of renal failure, and suspected or confirmed cerebrovascular bleeding, among others.15 

The labeling for all nonselective and selective NSAIDs contains boxed warnings for cardiovascular (CV) and GI risks.15 NSAID therapy is associated with an elevated risk of serious CV thrombotic events including myocardial infarction and stroke, which may be fatal, in patients with or without CV disease or CV disease risk factors.9,15 The elevation in CV risk can occur early after treatment initiation and may increase with prolonged therapy.15 An increase in blood pressure with NSAID administration contributes most significantly to the CV risk.9 Naproxen appears to have a lower CV risk in comparison to other available NSAIDs.9,13 Additionally, patients on NSAID therapy have an increased risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which may lead to death.15 These events can occur without warning at any time during therapy. Patients at an increased risk for serious GI adverse events include the elderly and those with a history of peptic ulcer disease and/or GI bleeding. Other potentially serious safety risks with NSAID administration include the development of nephrotoxicity, new or worsening hypertension, fluid retention and edema, anaphylactoid reactions, serious skin reactions, and anemia. 

Ongoing monitoring of NSAID therapy includes assessment of potential drug-drug interactions. NSAIDs are involved in numerous interactions.9,15 Clinicians can use freely available online drug interaction checkers (https://www.drugs.com/drug_interactions.html) or subscription-based databases to screen for and manage interactions. Some of the more clinically significant interactions involving NSAIDs include:15

  • Angiotensin-converting enzyme (ACE) inhibitors: concurrent administration can result in a reduction in renal function and a diminishment of the antihypertensive effect of ACE inhibitors
  • Anticoagulants: concurrent use may increase bleeding risk
  • Bisphosphonates: concurrent administration may result in an increased risk of GI ulceration and nephrotoxicity
  • Lithium: concurrent use may result in an increase in lithium serum concentration; modification of therapy may be required
Table 3. Usual Adult Dosing Regimens for Oral NSAIDs for Pain Relief.15
Generic Drug Name Dosage Recommendations
Non-selective NSAIDs
Diclofenac IR tablet: 50 mg 3 times daily; may administer 100 mg as an initial dose

No well-established maximum dose
Etodolac 200-400 mg every 6-8 hours; maximum dosage: 1000 mg/d
Fenoprofen 200 mg every 4-6 hours as needed; maximum dosage: 3200 mg/d
Flurbiprofen¥ 200-300 mg/d administered in 2-4 divided doses; maximum dosage: 100 mg as a single dose (in a multiple dose daily regimen)
Ibuprofen OTC: 1 gel cap or tablet every 4-6 hours while symptoms persist; if pain does not respond, 2 gel caps or tablets may be used, not to exceed 6 gel caps or tablets in 24 hours

RX: 200-400 mg every 4-6 hours or 200-800 mg 3-4 times daily; maximum dosage: 3200 mg/d
Indomethacin IR capsule/suspension: 75-150 mg/d in 3 or 4 divided doses

ER capsule: 75 mg once or twice daily

Duration of therapy: 7-14 days

No well-established maximum dose
Ketoprofen IR: 25-50 mg every 6-8 hours as needed; maximum dosage: 300 mg/d
Ketorolac Use of oral formulation is only indicated as continuation therapy to the IV or IM injection; oral formulation should not be given as an initial dose; total systemic therapy should not exceed 5 days

Initial dosage: patients weighing ≥ 50 kg: 20 mg as a first dose; patients weighing < 50 kg: 10 mg as a first dose

Maintenance dose: 10 mg every 4-6 hours as needed; maximum dosage: 40 mg/d
Meclofenamate 50-100 mg every 4-6 hours; maximum dosage: 400 mg/d
Mefenamic acid Initial dosage: 500 mg as a single dose

Maintenance dosage: 250 mg every 6 hours as needed

No well-established maximum dose
Meloxicam¥ Capsule: 5 mg once daily; some patients may benefit from increasing the dose to 10 mg once daily

ODT/tablet/suspension: 7.5 mg once daily: some patients may benefit from increasing the dose to 15 mg once daily

Maximum dosage: 10 mg/d (capsule); 15 mg/d (ODT/tablet/suspension)
Nabumetone¥ Initial dosage: 1000 mg as a single dose; patients weighing < 50 kg are less likely to require doses > 1000 mg/d

Adjust dose based on response up to 2000 mg/d in 1-2 divided doses
Naproxen OTC: 440 mg of naproxen sodium in any 8-12 hour period or 660 mg of naproxen sodium in a 24-hour period

RX: Dosage varies according to base and formulation; please refer to package labeling
Oxaprozin¥ 1800 mg/d or 26 mg/kg/d, whichever is lower

No well-established maximum dose
Piroxicam¥ 20 mg once daily

No well-established maximum dose
Sulindac¥ Initial dosage: 150 mg twice daily; maximum dosage: 400 mg/d
Tolmetin¥ Initial dosage: 400 mg 3 times daily

Maintenance dosage: 600-1800 mg daily in 3 divided doses; maximum dosage: 1800 mg/d
Combination products
Diclofenac sodium/ misoprostol¥ Diclofenac 50 mg/misoprostol 200 mcg 3 times daily
Naproxen/esomeprazole¥ 1 tablet (naproxen 375 mg/esomeprazole 20 mg or naproxen 500 mg/esomeprazole 20 mg) twice daily
Naproxen/sumatriptanβ Sumatriptan 85 mg/naproxen 500 mg; if a satisfactory response is not obtained at 2 hours, a second dose may be administered
COX-2 selective NSAID
Celecoxib Initial dosage: 400 mg followed by an additional 200 mg dose, if needed, on the first day

Maintenance dosage: 200 mg twice daily as needed

No well-established maximum dose
Abbreviations: COX-2, cyclooxygenase-2; ER, extended-release; IR, immediate-release; NSAID(s), nonsteroidal anti-inflammatory drug(s); ODT, orally disintegrating tablet; OTC, over-the-counter; RX, prescription.
¥NSAID not approved for acute pain; dosage regimen is for OA/RA.
ΒNSAID not approved for acute pain: dosage regimen is for migraine.


Aspirin is the most well-known salicylate; however, this agent is primarily used for its antiplatelet effects and less commonly utilized as an analgesic.10 The mechanisms of action and therapeutic effects of aspirin are dose-dependent.21 Low aspirin dosage regimens (75-81 mg/d) impact COX-1, inhibiting platelet generation of thromboxane A2 and resulting in an antiplatelet effect. Higher doses (650 mg to 4 g/d) inhibit COX-1 and COX-2 enzymes, resulting in a blockade of prostaglandin production and subsequent analgesic and antipyretic effects. The other available salicylates produce similar beneficial effects and are generally administered for the management of mild-to-moderate pain in patients with OA or RA.22 Table 4 summarizes the FDA-approved indications and adult oral dosage regimens for the salicylates. Major safety concerns with salicylates when used for pain relief include hypersensitivity, CV effects (eg, increase in blood pressure, heart failure exacerbation), risk for potential GI ulceration and bleeding, and renal impairment. These effects are similar to those observed with NSAID use. Of note, the risk of cross-sensitivity with other NSAIDs is significantly increased with aspirin than other salicylates. With regard to drug interactions involving salicylates, patients on concurrent medications with anticoagulant or antiplatelet effects should be monitored for signs and symptoms of bleeding. Additionally, patients concomitantly administered medications with nephrotoxic effects should be carefully monitored for changes in renal function and those receiving antidiabetic agents should have glucose levels closely followed.

Table 4. FDA-Approved Indications and Usual Adult Oral Dosage Regimens for Salicylates for Pain Relief.15
Generic Drug Name Indications Usual Dosage Regimen
Aspirin Temporary relief of pain caused by muscle aches and pains, menstrual pain, toothache pain, and minor aches and pains of arthritis IR: 325 mg to 1 gram every 4-6 hours as needed; maximum dosage: 4 g/d
Diflunisal OA/RA; treatment of mild-to-moderate pain Initial dosage: 1000 mg followed by 500 mg every 12 hours; some patients may require 500 mg every 8 hours

Maximum dosage: 1500 mg/d
Choline magnesium trisalicylate OA/RA; juvenile arthritis; treatment of acute painful shoulder; treatment of mild-to-moderate pain 2-3 grams daily in 2 or 3 divided doses

No well-established maximum dose
Salsalate OA/RA and related rheumatic disorders 3 g/d in 2-3 divided doses

No well-established maximum dose
Abbreviations: FDA, Food and Drug Administration; IR, immediate-release; OA, osteoarthritis; RA, rheumatoid arthritis.

Adjuvant agents or coanalgesics

Adjuvant agents or coanalgesics include various antidepressants, antiepileptics, skeletal muscle relaxants, and other medications. These are medications that are not primarily designed to control pain but may be employed for this effect. Many adjuvants are commonly administered to patients with neuropathic pain syndromes (eg, postherpetic neuralgia, diabetic neuropathy, fibromyalgia).13,23 However, some are also used for what are generally thought of as nociceptive conditions (eg, low back pain). Table 5 summarizes indications and usual adult dosage regimens for selected adjuvant analgesics. The varying degrees of serotonin and norepinephrine reuptake inhibition likely explain the analgesic properties of the tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs).13 The exact mechanisms of the analgesic effects for the anticonvulsants and skeletal muscle relaxants are not fully understood; however, cyclobenzaprine is structurally similar to amitriptyline.22 Lidocaine produces pain relief through a reversible nerve conduction blockade while capsaicin depletes and prevents the re-accumulation of substance P (the primary chemical mediator of pain impulses from the periphery to the central nervous system) in peripheral sensory neurons.

The TCAs and SNRIs have a boxed warning regarding an increased risk of suicidal thinking and behavior in children, adolescents, and young adults.22 Patients of any age who initiate antidepressant therapy should be closely monitored for clinical worsening. Other boxed warnings for adjuvant agents include serious dermatologic reactions, aplastic anemia, and agranulocytosis with carbamazepine and hepatotoxicity, fetal risk, and pancreatitis with divalproex sodium/valproate sodium. Additionally, the FDA has warned about serious breathing difficulties with the use of gabapentin and pregabalin, particularly among patients receiving concomitant opioids and other medications that depress respiration, those with pulmonary disorders, and the elderly.24 Clinicians should also be aware of more common adverse effects of the adjuvant agents. The anticholinergic effects of the TCAs (eg, dry mouth, blurred vision, urinary retention, constipation) are well known and undesirable; however, the sedative and antidepressant properties of these agents may be beneficial in patients with chronic pain experiencing anxiety and/or depression.9 The most commonly occurring adverse effects with the SNRIs include nausea, dry mouth, dizziness, headache, and excessive sweating.22 Anticonvulsants exhibit a wide range of potential adverse effects including sedation, weight gain/loss, renal stones, edema, forgetfulness, word-finding difficulty, teratogenicity, and sometimes poor balance. Tiredness, drowsiness, fatigue, and weakness are the most common adverse effects with skeletal muscle relaxants. Application site reactions (eg, erythema, pain, pruritus) may occur with transdermal lidocaine and capsaicin therapy.25,26 A transient increase in blood pressure has also been noted in patients during and shortly after transdermal capsaicin application.26 Drug interactions are of particular concern with carbamazepine and oxcarbazepine as both agents are strong cytochrome P450 (CYP) 3A4 inducers.9 Additionally, since sedation is a common adverse event for many of the adjuvant agents, clinicians should avoid concurrent administration of sedatives or medications with sedation as a prominent side effect.

Another unique issue regarding adjuvant agents for pain is the potential for misuse and abuse with gabapentin and pregabalin. Since approval, usage of both agents has expanded considerably and, in conjunction with the opioid epidemic in the United States, there have been increasing case reports and case series of inappropriate use. The majority of these reports have revealed particular concern for patients with a history of substance abuse.27-29 Clinicians considering prescribing gabapentinoids should carefully evaluate each patient for a previous history of drug abuse and be able to promptly identify signs of potential abuse and misuse.

Table 5. Usual Adult Dosage Regimens and Recommended Use for Adjuvant Nonopioids.4-8,13,22,25,26,30*
Generic Drug Name Recommended use Usual Dosage Regimen
Tricyclic antidepressants
Amitriptyline • Diabetic neuropathy
• Fibromyalgia (amitriptyline; “weak for”)
• Migraine prevention (amitriptyline probably effective)
25-100 mg once daily
Imipramine HCl 50-100 mg once daily or divided
Imipramine pamoate 75-100 mg once daily
Nortriptyline 75 mg once daily or divided
Duloxetine • Fibromyalgia (duloxetine, milnacipran; “weak for”)
• Chronic low back pain (duloxetine as a second-line pharmacologic option)
• Migraine prevention (venlafaxine probably effective)
• Knee, hip, and/or hand OA (duloxetine; conditionally recommended)
• Diabetic neuropathy (duloxetine)
60 mg once daily
Milnacipran 50 mg twice daily
Venlafaxine IR: 75 mg 1-3 times daily ER: 75-150 mg once daily
Carbamazepine • Diabetic neuropathy (pregabalin, gabapentin)
• Fibromyalgia (pregabalin; “weak for”)
• Migraine prevention (divalproex sodium, valproate sodium, and topiramate established efficacy; carbamazepine possibly effective)
200-400 mg twice daily
Divalproex sodium; valproate sodium DR: 250 mg twice daily initially; titrate as needed up to a maximum dose of 500 mg twice daily

ER: 500 mg once daily for 1 week, then 1000 mg once daily
Gabapentin IR: 600-1200 mg 3 times daily

ER: 1800 mg once daily or 600 mg twice daily dependent upon product
Oxcarbazepine IR: 300-600 mg twice daily

ER: 600-2400 mg once daily
Pregabalin IR: 75-300 mg twice daily or 50-200 mg 3 times daily

ER: 330-660 mg once daily
Topiramate IR: 25 mg every evening for 1 week, then 25 mg twice daily for 1 week, then 25 mg orally every morning and 50 mg every evening for 1 week; and then 50 mg twice daily

ER: 25 mg once daily for 1 week, then 50 mg once daily for 1 week, then 75 mg once daily for 1 week, and then 100 mg once daily
Skeletal muscle relaxants
Baclofen • Acute or subacute low back pain; option if pharmacologic therapy is necessary
• Fibromyalgia (cyclobenzaprine; “weak for”)
5 mg 3 times daily initially, increase slowly every 3 days by 5 mg 3 times daily up to 40-80 mg/d given in 3-4 divided doses
Cyclobenzaprine IR: 5 mg 3 times daily; if needed, may increase to 7.5 or 10 mg 3 times daily

ER: 15 mg once daily; some patients may require 30 mg once daily
Topical pain medications
Lidocaine 5% patch • Relief of pain associated with post-herpetic neuralgia
• Knee OA (capsaicin; conditionally recommended)
Apply the prescribed number of patches (maximum of 3), only once for up to 12 hours within a 24-hour period
Capsaicin 8% patch Single, 60-minute application of up to 4 patches; may be repeated every 3 months or as warranted by the return of pain (not more frequently than every 3 months)
*Usual dosing regimens were summarized from The Medical Letter Nonopioid Drugs for Pain, Clinical Pharmacology, and product labeling as appropriate.

Abbreviations: DR, delayed-release; ER, extended-release; HCl, hydrochloride; IR, immediate-release; OA, osteoarthritis; SNRI(s), serotonin norepinephrine reuptake inhibitor(s).

Patient Counseling

The FDA has compiled a guide for safe use of pain medicine that contains key patient counseling points.31 First, it is important to reinforce with patients that nonopioid analgesics are effective and safe when used as directed; however, misuse can result in serious adverse effects. Patients should follow instructions carefully and not alter a recommended dosage regimen without talking to their provider. Furthermore, patients should be counseled not to share pain medications with anyone else and avoid taking multiple medications with the same active ingredient at the same time. Specific key counseling points for acetaminophen and NSAIDs per the FDA guide are summarized in Table 6.

Table 6. Key Patient Counseling Points for Acetaminophen and NSAIDs.31
Medication Counseling points
Acetaminophen • Exceeding the recommended dose will not provide further analgesic relief and may even be extremely dangerous
• Overuse of acetaminophen can lead to significant hepatic damage and even death.
• Individuals who drink ³ 3 alcoholic drinks per day while using acetaminophen-containing medications may be at an increased risk for hepatic damage
NSAIDs • Overuse of NSAIDs can result in stomach bleeding
• The risk of stomach bleeding is increased in patients > 60 years of age, those concurrently taking blood thinners or steroids, those with a history of stomach bleeding or ulcers, and those with other bleeding problems
• Renal damage can also occur with NSAID use
• Patients at an increased risk of renal damage include patients > 60 years of age, those with hypertension, heart disease, or pre-existing kidney disease, and those concurrently taking a diuretic
Abbreviations: NSAID(s),nonsteroidal anti-inflammatory drug(s).


Pharmacologic therapy for the management of acute and chronic pain conditions may be broadly classified into 2 categories: opioid analgesics and nonopioid analgesics. Traditional nonopioid analgesics include acetaminophen, NSAIDs, and salicylates as well as adjuvant agents that are not primarily designed to control pain, but may be employed for this effect (eg, certain antidepressants and anticonvulsants). Nonopioid analgesics have a key role in pain management with evidence-based clinical practice guidelines supporting their use based on varying strengths of evidence.

Acetaminophen is an effective and safe analgesic that is inexpensive, widely prescribed, and available in numerous OTC and prescription formulations. The main safety concern with its use is the occurrence of hepatotoxicity when exceeding the maximum recommended total daily dose. Nonsteroidal anti-inflammatory drugs are also extensively prescribed, effective, and safe nonopioid analgesics primarily used for the management of pain associated with musculoskeletal and joint disorders. These agents are commercially available in specific combination products and a variety of formulations. Their main safety concerns include potentially increased risks for GI bleeding, renal damage, and CV events. The salicylates produce beneficial analgesic, anti-inflammatory, and antipyretic effects (similar to NSAIDs) and are generally given to patients with mild to moderate pain associated with OA or RA. Adverse effects are similar to those observed with NSAID use. 

Adjuvant nonopioid agents are generally given to patients with neuropathic pain syndromes; however, some may be administered to patients with conditions generally thought to be nociceptive in nature. These agents have a wide variety of boxed warnings and serious adverse effects. The occurrence of sedation is a common adverse effect with the majority of adjuvant agents. Clinicians should avoid concomitant prescribing of sedatives or medications with sedation as a prominent side effect with the majority of adjuvant agents.


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