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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.
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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.

Last updated on: August 7, 2015
First published on: April 1, 2011