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13 Articles in Volume 11, Issue #3
Advances in Cranial Electrotherapy Stimulation
Chronic Migraine: An Interactive Case History, Part 3
Cost-effectiveness Of Treatments for Low Back Pain
Electrical Me
Lessons From The Father of Electromedicine — Dr. Luigi Galvani
Medications for Chronic Pain—Nonopioid Analgesics
Pulsed Radio Frequency Energy As an Effective Pain Treatment
The Role of Body Posture In Musculoskeletal Pain Syndromes
The Role of Body Posture In Musculoskeletal Pain Syndromes
Therapeutic Laser for the Treatment of Chronic Low Back Pain
Tolerance to Opioids
Understanding Electromagnetic Treatments
Update: Clinical Challenges in the Diagnosis And Management of Fibromyalgia

Medications for Chronic Pain—Nonopioid Analgesics

In part 1 of a 3-part series reviewing medications for the treatment of chronic pain, the authors review specific guidelines for low back pain, osteoarthritis, and migraine.

Pain is known to affect physical and mental functioning, and uncontrolled pain can have a significant impact on a patient’s quality of life.1 Both direct and indirect medical costs have been shown to rise as a result of uncontrolled pain because of increased provider and hospital visits, lost time from work, and loss of productivity and concentration at work.

Data from the National Health and Nutrition Examination Survey show that approximately 26% of Americans aged 20 years and older, or an estimated 76.5 million people, have had pain that persisted for more than 24 hours in the prior 30 days.2 In addition, the majority of patients (60%) aged 60 years and older who reported experiencing pain for longer than 24 hours stated that their pain actually lasted for a year or more. Common types of pain reported by adults include low back pain, joint pain, and migraine/severe headache pain.

Pain can be treated with a variety of nonpharmacologic and pharmacologic interventions. Pharmacologic interventions include nonopioid analgesics (eg, acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDs]), opioid analgesics, and other treatments, such as certain antidepressants and anticonvulsants. This is part 1 of a 3-part series that reviews medications for chronic pain. Nonopioid analgesics are the focus of this initial review.

Place in Therapy of Nonopioid Analgesics

Nonopioid analgesics are preferred treatments in a multitude of practice guidelines; a brief overview of specific guidelines for low back pain, osteoarthritis, and migraine is presented here because these are the most common types of pain identified by adults who participated in the National Health and Nutrition Examination Survey (see Table 1).2-7

Table 1. Select Practice Guidelines for Selection of Nonopioid Analgesics


Acetaminophen (APAP) is one of the most commonly used nonopioid analgesics because it is available in hundreds of over-the-counter (OTC) products and in combination with opioid analgesics as a prescription drug. The drug has both analgesic and antipyretic activity, and its effects have been noted to be similar to those of aspirin.8

Acetaminophen exerts its mechanism of action via one or more central nervous system pathways.9 These proposed mechanisms include a serotonergic pathway, a central cyclo-oxygenase (COX)-3 mechanism, and a cannabinoid-mediated mechanism. It has poor inhibition of the COX-1 and COX-2 isoforms, which distinguishes it from NSAIDs. Acetaminophen’s antipyretic effects are attributed to inhibition of the activity of the hypothalamic heat-regulation center.

In the United States, acetaminophen is available in oral and rectal formulations and, most recently, as an intravenous product.10 The recommended dosing in adults is 325 mg to 650 mg by mouth or per rectum every 4 to 6 hours, not to exceed 4 g in a 24-hour period. For children, acetaminophen is dosed based on weight, with the recommended dose being 10 mg/kg every 4 to 6 hours.

Unlike NSAIDs, acetaminophen does not produce any anti-inflammatory effects, has no antiplatelet effects, and does not damage the gastrointestinal (GI) mucosa.8,9 In addition, acetaminophen is rarely associated with renal toxicity and is considered safe for both pregnant and breast-feeding women.10

Hepatic toxicity is the main adverse event associated with acetaminophen. This is generally observed when adults or adolescents ingest more than 7.5 g to 10 g in a single dose or during an 8-hour period.9 Patients with chronic alcoholism and those with liver disease are particularly susceptible.8 Patients who consume 3 or more alcoholic drinks daily should limit their use of acetaminophen, with an intake of no more than 2 g per day recommended for chronic alcoholics.10 Another concern with acetaminophen use is the occurrence of hypersensitivity reactions, but these reactions are rare.

Acetaminophen has minimal drug interactions, but one that often is overlooked is the interaction between acetaminophen and warfarin.8,10 Acetaminophen appears to increase the antithrombotic effects of warfarin. This is a dose-dependent interaction, with doses of acetaminophen of no more than 1950 mg per week not resulting in clinically important changes, but higher doses being of concern.10 For patients receiving warfarin, it is recommended to limit acetaminophen use and monitor coagulation parameters 1 to 2 times per week when starting or stopping higher doses of acetaminophen.

Table 2. Summary of FDA-labeled Indications for Oral Selective and Nonselective NSAIDs

Table 3. General Adult Dosing Range for Selective and Nonselective Oral NSAIDs for Pain Control

Recent FDA Action

In January 2011, the FDA announced that it was asking all manufacturers of combination prescription drug products that contain acetaminophen to limit the amount of acetaminophen in these products to no more than 325 mg.11 This change was a result of numerous reports of liver injury and rare reports of anaphylaxis and other types of allergic reactions occurring with use of acetaminophen-containing products. Many cases of liver injury were a result of unintentional overdoses of acetaminophen, with patients unaware that various products contained the drug or of the recommended maximum dose of 4 g per day.

The FDA is also requiring a boxed warning on all prescription products that contain acetaminophen, highlighting the potential for hepatic injury and allergic reactions with this drug. This change does not affect over-the-counter (OTC) products, but the FDA noted that it is continuing to evaluate ways to reduce the risks associated with OTC acetaminophen products.

Nonselective NSAIDs

Nonselective NSAIDs exhibit analgesic, antipyretic, and anti-inflammatory properties.8 There are numerous nonselective NSAIDs available, with each agent indicated for various conditions, such as osteoarthritis, rheumatoid arthritis, and/or mild to moderate pain (see Table 2).10 Some products are even available as combination agents with misoprostol or esomeprazole for patients at high risk for GI adverse events, or in combination with sumatriptan for management of acute migraine pain. NSAIDs exert their mechanism of action by inhibiting COX, a key enzyme responsible for the biosynthesis of prostanoids, including prostaglandins.8,12 Nonselective NSAIDs inhibit both COX-1 and COX-2. The COX-1 isoform is constantly expressed in tissue and regulates protection of the gastric mucosa, platelet activation, and renal function. Inhibition of COX-1 is thought to be largely responsible for some of the adverse events associated with NSAIDs. In contrast, inhibition of the COX-2 isoform is primarily responsible for the anti-inflammatory effects of NSAIDs.

The analgesic effects of NSAIDs are dose dependent, with patients able to start with lower OTC doses and then given higher-strength prescription products if needed.12 These agents do have an analgesic ceiling effect; therefore, increasing the dose to above recommended maximum limits only increases the potential for adverse events and will not result in additional pain control.8 A positive attribute of NSAIDs when compared with narcotic analgesics such as opioids is that these agents do not produce physical or physiologic dependence and can be discontinued abruptly if needed. A review of recommended doses for available oral nonselective NSAIDs for pain control is presented in Table 3.10

Safety Considerations

Frequently reported adverse effects with NSAIDs include nausea, diarrhea, abdominal pain or cramps, dyspepsia, constipation, rash, dizziness, headache, and drowsiness, with GI-related adverse effects the most common complaints reported by patients.10 In 2005, the FDA concluded that all NSAIDs cause serious GI events, such as bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine.13 These events can occur without warning at any time during NSAID therapy, with the elderly at greatest risk. Estimates suggest that upper GI ulcers, gross bleeding, or perforation occur in approximately 1% of patients given NSAID therapy for 3 to 6 months and 2% to 4% of patients treated for 1 year.10 Longer duration of use increases the likelihood of developing a serious GI event.

Cardiovascular events, such as thrombosis, myocardial infarction, and stroke, are another serious safety concern with NSAID administration. Per the FDA, all NSAIDs may have a similar potential for increasing the risk for serious cardiovascular events.13 As such, the product labeling for all products was updated to state this risk. This risk may be increased with prolonged duration of therapy and in patients with existing cardiovascular disease or risk factors for the development of cardiovascular disease. The boxed warning for NSAIDs also includes a statement about NSAIDs being contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. This contraindication stems from data that found an increased incidence of cardiovascular events in patients using different COX-2–selective NSAIDs for the treatment of pain in the first 10 days following CABG surgery.14

Other serious adverse events reported with NSAIDs include the onset of new hypertension or worsening of preexisting hypertension, fluid retention and edema, renal papillary necrosis and other renal injury, anaphylactoid reactions, serious skin reactions (eg, exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis), elevations of 1 or more liver-associated enzymes, and anemia. Aseptic meningitis with fever and coma has been observed on rare occasions.13

There are multiple drug interactions involving NSAIDs. A few of the major interactions include:13

  • Angiotensin-converting enzyme (ACE) inhibitors: concurrent use results in a blunted antihypertensive effect
  • Anticoagulants: use with NSAIDs increases bleeding risk
  • Bisphosphonates: concomitant use increases gastric ulcer risk
  • Lithium: concurrent NSAID use increases lithium levels

In addition, there is a specific interaction between ibuprofen and aspirin, which may reduce the cardioprotective effects of aspirin. Concurrent ibuprofen and aspirin therapy should be avoided.15

COX-2 Inhibitor: Celecoxib

Celecoxib (Celebrex) is known as a selective NSAID because it exerts anti-inflammatory, analgesic, and antipyretic effects due to inhibition of prostaglandin synthesis, primarily via inhibition of COX-2.16 This mechanism of action differs from that of the nonselective NSAIDs, which produce similar effects through inhibition of both COX-1 and COX-2 isoforms. As noted previously, the COX-1 isoform regulates protection of the gastric mucosa.8,12 Because celecoxib does not inhibit COX-1, a theoretical advantage of administering this agent is reduced GI adverse events compared with nonselective NSAIDS with similar analgesic efficacy (see Table 2 and 3).

Celecoxib is indicated for use in osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, and primary dysmenorrhea.16 Depending on indication for use, the usual dosage range for celecoxib varies from 50 mg to 200 mg twice daily. Celecoxib, similar to all other NSAIDs, carries a boxed warning regarding an increased risk of serious cardiovascular and GI events despite the potential for fewer GI adverse events compared with nonselective NSAIDs. Given these risks, the FDA encourages practitioners to use the lowest effective dose of celecoxib for the shortest duration consistent with the treatment goals of the individual patient.13

Table 4. Salicylates for Pain


Salicylates include aspirin, the modified salicylate diflunisal, and nonacetylated salicylates such as choline magnesium trisalicylate and salsalate.17 General information related to the salicylates, including average analgesic dosage regimens, is summarized in Table 4. Of note, aspirin is primarily administered for its platelet-inhibiting effects and is rarely used as an analgesic.

Counseling Pearls

The FDA has published “A Guide to Safe Use of Pain Medicine” and “Acetaminophen and Liver Injury: Q & A for Consumers.”18,19 Numerous counseling tips are summarized in these documents to help patients safely use acetaminophen and NSAIDs (see Table 5).


Nonopioid analgesics, such as acetaminophen, NSAIDs, and salicylates, may be effective therapeutic options for chronic pain control for a variety of indications. Acetaminophen is one of the most commonly used nonopioid analgesics that is available in a variety of OTC and prescription products. Nonselective and selective (ie, celecoxib) NSAIDs are also common nonopioid analgesics that produce dose-dependent effects with the potential for serious GI and cardiovascular events. Salicylates are effective options for mild to moderate pain; however, aspirin is used primarily to inhibit platelet activity at low doses, and most of the other available salicylates are not commonly used agents.


Last updated on: August 7, 2015
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