Appropriate treatment of pain requires an understanding of the characteristics of pain, including the severity and the nature of the pain—for example, acute versus chronic pain or nociceptive versus neuropathic pain. Appropriate treatment requires an understanding of the efficacies of the available agents in different pain models, and their adverse events, to best match them to the type of pain. While numerous classes of drugs are used to treat pain, 3 categories in particular—acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids—are most often used for the treatment of pain, along with adjuvants (eg, muscle relaxants, anticonvulsants). Each of these drugs is associated with different adverse events and with varying degrees of efficacy. In general, acetaminophen is the least potent, while NSAIDs and opioids offer stronger analgesic effects. At the same time, acetaminophen use can cause acute liver failure, and NSAIDs are associated with serious complications impacting the gastrointestinal, cardiovascular, and renal systems. Opioids can cause cognitive deficiency, motor impairment, and respiratory depression, among other problems; they also represent a significant addiction risk in certain groups of patients. This article reviews the safety and efficacy of NSAIDs relative to other therapeutic agents in the treatment of 4 common types of pain, summarizes clinical treatment guidelines in these types of pain, and compares the relative roles of NSAIDs, acetaminophen, and opioids in treating pain.
Am J Manag Care. 2013;19(16 suppl):S261-S266There are many different kinds of pain, and many different ways of classifying pain. There is acute and chronic pain, nociceptive and neuropathic pain, migraine, postoperative, musculoskeletal, and cancer pain, among many other painful experiences. There are also numerous types of therapeutic agents for treating pain. However, 3 general categories of analgesic agents are frequently used for the most common types of pain: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Other agents, such as the gamma-aminobutyric acid analogue gabapentin, and the anticonvulsants (eg, carbamazepine, zonisamide), are recommended for the treatment of neuropathic pain.1-3
Within the NSAID category and the opioid category, there exists a range of specific agents (eg, selective versus non-selective NSAIDs) with varying levels of efficacy and risk of adverse events. Each of the 3 analgesic categories is associated with potentially serious side effects that require caution. Acetaminophen has been shown to cause liver damage.4 NSAIDs are associated with varying degrees of gastrointestinal (GI), cardiovascular, and renal adverse events.3 Opioids can cause respiratory depression and cognitive and motor impairment, and can also potentially cause dependence and addiction.3,5 Table 11,6-14 summarizes the indications, efficacy, and accessibility of the 3 main categories of medications for the management of pain, along with safety concerns associated with their use. Safety concerns associated with acetaminophen and opioids will be discussed in more detail later in this article, and safety concerns associated with NSAIDs are discussed in more detail in another article in this supplement.15
Considering that pain is complex, and that agents for treating pain are diverse in their efficacy and safety, it is advisable that the selection of an appropriate analgesic be based upon an evaluation of the characteristics of a particular pain experience—acute or chronic, musculoskeletal or postoperative, etc—and a measurement of the severity of that pain. Once the nature of the pain is understood, it can be matched against the various available treatments based on mechanisms of action, efficacy, and safety, as well as the patient’s individual risk factors.1,16
Clinical Guidelines and NSAID Utility in Different Pain Types
Clinical guidelines for managing acute pain in the perioperative setting, updated in 2012 by the American Society of Anesthesiologists Task Force on Acute Pain Management, recommend a multimodal approach to postoperative pain. The primary agents recommended for use in this approach are acetaminophen, nonselective NSAIDs as well as selective NSAIDs (ie, cyclooxygenase-2 [COX-2] inhibitors), and gabapentin and pregabalin.17
The use of a single dose of the COX-2 inhibitor celecoxib in the treatment of acute postoperative pain was the subject of a Cochrane review, which found that 33% of patients receiving celecoxib 200 mg, and 44% receiving 400 mg, experienced at least 50% pain relief, compared with between 1% and 11% of patients receiving placebo. Overall, the frequency of adverse events was similar in the celecoxib and placebo groups.18
A single dose of ibuprofen, a non-selective NSAID, was observed, in a Cochrane review, to confer at least 50% pain relief in approximately half of patients with moderate to severe postoperative pain, and adverse events were similar to placebo.19 Aspirin, also the subject of a Cochrane review in postoperative pain, was found to offer a 50% or greater reduction in pain in 39% of those with moderate to severe pain, compared with 15% of those in the placebo group. The efficacy of aspirin was considered equivalent to that of acetaminophen. Adverse events were statistically similar for those taking a lower aspirin dose, 600 mg to 650 mg, compared with placebo. However, patients who took a higher dose of aspirin (900 mg to 1000 mg) experienced adverse events at more than twice the rate of patients receiving placebo (26% vs 12%). The most common events in the aspirin group were drowsiness, dizziness, nausea, vomiting, and gastric irritation.20
Low Back Pain
The joint guidelines from the American College of Physicians (ACP) and the American Pain Society (APS) recommend that, in most cases, first-line treatment of low back pain (LBP) should consist of an NSAID or acetaminophen. In considering the relative safety and efficacy profiles of different pain medications, the ACP/APS guidelines note that, compared with NSAIDs, acetaminophen is a slightly weaker analgesic. Acetaminophen is recommended as a first-line therapy for acute and chronic LBP. The guidelines also point out the risk of aminotransferase elevations with acetaminophen treatment in doses greater than 4 grams per day. NSAIDs are noted in the guidelines for providing greater pain relief than acetaminophen, with the caveat that they are associated with GI and renovascular risks. Consequently, clinicians are advised to recommend to their patients the lowest effective NSAID dose for the shortest duration. In addition, strategies for minimizing possible side effects should be implemented for patients at higher risk for complications, including lower NSAID doses and coadministration of a proton pump inhibitor.16
In cases of more severe pain, in which NSAID or acetaminophen treatment provides inadequate pain relief, other options are available. When pain is severe and disabling, the ACP/APS guidelines cautiously recommend opioid analgesics, or tramadol may be appropriate, although risk of addiction or dependence is noted and periodic reassessment for the need of continued use and the efficacy of opioid treatment is recommended. Tricyclic antidepressants may also be prescribed to those patients experiencing chronic LBP. Skeletal muscle relaxants may provide short-term relief in cases of acute LBP, although central nervous system side effects are a concern with this class of drugs.16,21
Several classes of drugs are recommended by the American College of Rheumatology (ACR) for osteoarthritis (OA) pain in the hand, knee, and hip. For hand pain, topical capsaicin and NSAID s (topical or oral, including COX-2 inhibitors) are suggested as first-line therapy. Acetaminophen is not recommended for hand OA. Tramadol, a synthetic opioid, is also an option, although the use of conventional (nonsynthetic) opioids is not recommended. For patients aged 75 years or more, topical NSAIDs are preferred to oral NSAIDs. Primary recommendations for knee OA are almost the same as those for hand OA, except that acetaminophen and intra-articular corticosteroid injections are added options, while no recommendation regarding opioids is given. For hip OA, the ACR recommends acetaminophen, oral NSAIDs, tramadol, and intra-articular corticosteroid injections. It should be noted that opioid treatment is strongly recommended in cases of knee or hip pain that have not responded to nonpharmacologic or other pharmacologic treatment.22
The ACR recommendation is consistent with a 2004 meta-analysis by Lee et al, which found that NSAIDs were superior to acetaminophen for reducing certain types of OA pain.23 Similarly, a 2006 Cochrane review comparing the safety and efficacy of acetaminophen with placebo and acetaminophen to NSAIDs (eg, ibuprofen, diclofenac, celecoxib, naproxen) found that NSAIDs were superior to acetaminophen using Western Ontario and McMaster Universities (WOMAC) OA scores for pain and total outcomes. (WOMAC is a common measurement of pain, stiffness, and function that can be indicative of response to treatment and may predict treatment response.) The review also found that acetaminophen was superior to placebo on several pain measures (eg, rest pain, pain on motion); however, there were no significant WOMAC score differences between treatments.24-26
The Cochrane review found that when they compared only ibuprofen and naproxen with acetaminophen, ibuprofen and naproxen carried a 1.47 (95% confidence interval [CI], 1.08-2.00) relative risk (RR) for GI events. The incidence of GI events was not significantly elevated in users of COX-2 inhibitors (RR, 0.98 [95% CI, 0.80-1.20]) or in all NSAID users combined (RR, 1.11 [95% CI, 0.94-1.31]) compared with acetaminophen.24
Guidelines for the treatment of migraine typically address one or both of the major targets for pharmacologic intervention: prevention of migraine and treatment of migraine pain. For migraine prevention, the American Academy of Neurology (AAN) and American Headache Society (AHS) joint guidelines recommend a number of anticonvulsant agents, b-blockers, and triptans, among other classes of drugs.27 The AAN and AHS have also produced a guideline for NSAIDs in migraine prevention, showing some potential preventive efficacy associated with certain NSAIDs, such as fenoprofen, ibuprofen, and naproxen.28
A 2013 Cochrane review of clinical studies of the NSAID ibuprofen in the treatment of migraine found it to be an effective treatment for migraine pain. Approximately onefourth of people with migraine pain experienced a reduction from severe or moderate pain to no pain within 2 hours of taking a 400-mg dose of ibuprofen versus less than half that number among individuals given placebo. A reduction in pain intensity from moderate-severe to mild was seen in 57% of patients receiving ibuprofen compared with 25% of those taking placebo. Adverse events were generally mild, transient, and no more frequent than for patients in placebo groups.29
A 2010 meta-analysis of studies of naproxen in migraine found this NSAID to be significantly superior to placebo for acute treatment of pain, although it was also associated with significantly greater side effects. The pooled risk ratio for achieving headache relief with naproxen within 2 hours of administration was 1.58 (P <.00001), while the risk ratio of being pain free at 2 hours was 2.22 (P =.0002). At the same time, the risk of an adverse event with naproxen was 1.29 (P = .02), with dizziness, nausea, dyspepsia, and abdominal pain being the most common adverse events.30
Role of Acetaminophen
Acetaminophen is used to treat many different types of pain, and is considered appropriate for pain severity that is mild to moderate.31 However, there are concerns about the safety of acetaminophen, particularly when administered at higher doses. Acetaminophen-related liver injury is a leading cause of acute liver failure; a 2007 Centers for Disease Control and Prevention (CDC) population-based report estimated that there are 1600 cases of all-cause acute liver failure annually, the majority of which are attributed to acetaminophen use.32 in 2011, the US Food and Drug Administration (FDA) issued a safety communication limiting the amount of acetaminophen in prescription products to 325 mg per dosage unit.33 The FDA maintains that the maximum adult daily dose of acetaminophen in over-the-counter products should not exceed 4000 mg.7
The FDA released a consumer 2013 guide entitled “don’t double up on Acetaminophen,” which states that more than 600 prescription and over-the-counter products, for pain relief and reducing fever, contain the drug. The FDA statement cautions consumers to check the ingredients of their medications to avoid acetaminophen overdose, the symptoms of which can take days to emerge.34
Role of Opioids
In general, opioids are recommended only for severe pain (ie, visual analogue scale scores of at least 7), as in the postsurgical setting, and other situations in which NSAids, acetaminophen, or other treatments provide inadequate pain relief. Opioids are associated with serious side effects, including respiratory depression, motor and cognitive impairment, sedation, and the development of tolerance. in addition, sustained use of opioids can result in the development of an increased sensitivity to pain, known as opioid-induced hyperalgesia.5,35
A 2004 meta-analysis of 18 randomized clinical trials of opioids for the treatment of various types of noncancer pain observed that the mean reduction in pain intensity ranged from approximately 20% to 30% for OA pain, but was approximately 10% for musculoskeletal pain. moreover, 3 out of 8 studies showed either improvement in functional status or a reduction in disability with use of opioid analgesics. Quality-of-life (QoL) improvements were seen in 1 out of the 3 studies that measured QoL.36
The use of opioids is an area of long and continuing debate in both the medical and regulatory arenas. Opioids are associated with a number of other risks such as abuse, addiction, and diversion, which has resulted in tighter legal regulations regarding their prescription and distribution. In addition, there have been widespread concerns that the use of opioids is increasing at an unwarranted and possibly hazardous rate. Mafi et al conducted a study of treatments for back pain using data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey collected between 1999 and 2010 to assess treatment patterns in 23,918 physician visits. The unadjusted results showed that the percentage of patients who received a prescription for opioids during an office visit for back pain increased from 19.3% in 1999-2000 to 29.1% in 2009-2010 (P <.001). During the same period of time, the use of NSAIDs for back pain decreased from 36.9% to 24.5% ( <.001) (Table 2).37
With the increased use of opioids, there has been a concurrent increase in opioid-related overdoses and deaths. According to data published by the CDC, abuse of prescription painkillers led to over 475,000 visits to the emergency department in 2009.12 CDC data on poisoning deaths indicate that the number of deaths related to opioid use increased nearly 4-fold from 4030 in 1999 to 14,800 in 2008.38 In 2008, the number of overdose deaths involving the use of opioid pain relievers exceeded the number of deaths caused by heroin and cocaine combined. The majority of people who abuse prescription painkillers did not have a prescription for the medication (Figure).12
Author affiliation: International Clinical Research Institute, Overland Park, KS.
Funding source: This supplement was sponsored by Iroko Pharmaceuticals, LLC.
Author disclosure: Dr Nalamachu reports serving as a consultant/advisory board member for Iroko Pharmaceuticals, LLC. He also reports receipt of honoraria and lecture fees from Iroko Pharmaceuticals, LLC.
Authorship information: Analysis and interpretation of data; critical revision of the manuscript for important intellectual content; and technical support.
Address correspondence to: E-mail: Nalamachu@gmail.com.
No analgesic approach, whether pharmacologic or nonpharmacologic, is without risk, and no 1 drug is appropriate in all cases of pain. The management of pain requires that clinicians prescribe or recommend those interventions that will best address the pain while avoiding harm. In the majority of cases, an NSAID is likely to be the first line of therapy, in part because it has superior efficacy compared with acetaminophen, but does not incur the same degree of risk as some of the more potent drugs. There are risks inherent with NSAID use, but this is also true of acetaminophen—for a typically smaller therapeutic effect—and of opioids, which are associated with a spectrum of concerns of which side effects represent only 1 significant contributor. Looking to the near future, the potential to lower the risk of adverse events with NSAIDs by lowering the dose, while maintaining efficacy, represents a hopeful direction in the treatment of pain.