Opioid Prescribing and Monitoring - (Second Edition)
Primary Care Models for Pain Management

Effective Alternative Treatments and How to Assess Whether They’re Working

The recent emphasis on decreasing the use of opioid analgesics has contributed to an unfortunate side effect: many patients are struggling to receive adequate pain management. This unintended consequence can profoundly affect the quality of life and function of millions of patients. In this chapter, the authors review some effective opioid alternatives that may help providers manage their patients’ chronic pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of medications within the available pain pharmacotherapy arsenal. Other alternatives, such as acetaminophen and topical medications, can be highly effective in sparing opioids or in targeting localized pain generators.


NSAIDs encompass a class of medications available over the counter (OTC) or via prescription that are widely used to treat inflammation, pain, and fever. The modern age of NSAID agents began in 1965 with the approval of indomethacin, the first non-aspirin NSAID.1 While still demonstrating considerable gastrointestinal (GI) upset, indomethacin showed enormous improvement over aspirin in reducing “pill burden” and acid load, and in increasing overall tolerability.

In 1971, British pharmacologist Sir John Vane described inhibition of prostaglandin synthesis as the mechanism of action for aspirin and NSAIDs, and he won the Nobel Prize in 1982 for his work.2 Prostaglandins help regulate a variety of physiological functions, including inflammation, pain, fever, platelet aggregation, mucosal protection in the GI tract, and renal function.3,4 NSAIDs inhibit biosynthesis of prostaglandins by preventing the substrate arachidonic acid from binding to the active site of cyclooxygenase (COX) enzymes.5

The 2 known isoforms of the COX enzyme, COX-1 and COX-2, each have distinct physiological roles. COX-1 is constitutively expressed in nearly all cells; it regulates function in the GI tract, kidneys, and platelets. COX-1 produces vasoactive substances such as thromboxane and prostacyclin in equal amounts, thereby maintaining a balance.6 COX-2 is expressed in the brain, kidneys, and blood vessels—the areas most susceptible to thrombotic events. Expression of COX-2 can be induced by cytokine release due to injury or inflammation.7-11

Vane’s discovery sparked an NSAID research renaissance that yielded
15 new agents from 1976 to 1991. While more than 25 NSAIDs are now available, physicians should recognize that they belong to different pharmacologic classes with distinct properties (Figure 1, page 60). Each agent also has unique features such as varying levels of selectivity, efficacy, and toxicity.


Both aspirin and NSAIDs bind to the same COX-1 enzyme and can increase bleeding risk; the profound difference is how they bind and how long their effects last. NSAIDs bind reversibly to COX-1 enzymes and inhibit platelet function for the duration of binding, which is usually shorter than their duration of action. This means that NSAIDs must be taken consistently to increase the risk of bleeding. Approximately 5 half-lives (usually 1 to 4 days depending on the specific NSAID) are sufficient to completely clear the medication from the body and eliminate any associated bleeding risk. Aspirin, however, binds irreversibly to COX-1 enzymes. Since platelets are anucleated, they do not recover and remain inhibited for their entire life cycle (7 to 10 days).12 Therefore, the bleeding risk of aspirin, even at low doses, is profoundly higher than that of any other NSAID.

Despite these differences, patients are often asked to stop taking NSAIDs 7 to 10 days before a procedure or surgery, resulting in unnecessary discomfort and decreased ability to function. Patients who require aspirin for its cardio-protective effects should be counseled to take it at least 30 minutes prior to non-aspirin NSAIDs to receive the intended benefits.12

Many clinicians assume aspirin and NSAIDs are the same. This conflation can lead to inappropriate use and avoidable suffering. Aspirin is rarely used as an anti-inflammatory in modern medicine because very high doses (≥ 3 g/day) are required for efficacy but are generally not well tolerated.13,14 Instead, aspirin is primarily used as a cardioprotective antiplatelet agent, for which it is highly effective at even low doses (≤ 81 mg/day).12

Adverse Effects and FDA Warnings

Although the potential adverse effects of NSAIDs have been extensively studied and reported on over the past 20 years (see below), widespread confusion still exists about their risks and benefits.

In 2005, the US Food and Drug Administration (FDA) released a boxed warning for all NSAIDs that stated, “NSAIDs are associated with an increased risk of adverse cardiovascular [CV] thrombotic events including myocardial infarction and stroke; and NSAIDs may increase risk of GI irritation, inflammation, ulceration, bleeding, and perforation. These events may occur at any time during therapy and without warning.”15

In July 2015, the FDA strengthened the warnings for CV events with NSAIDs as a class effect.16 Every new NSAID approved over the past 20 years has attempted to improve the safety of these medications by lowering their GI or CV risk profile. The preferred hypothesis for many NSAID side effects is an imbalance between prostacyclin and thromboxane.6,17

Gastrointestinal Adverse Effects

Because COX-1 inhibition directly affects platelet aggregation, the degree to which an NSAID inhibits COX-1 plays an integral role in determining a patient’s bleeding risk.6,12 Strong COX-1 inhibitors, with > 50x selectivity (eg, indomethacin, tolmetin, piroxicam, and sulindac), are associated with more GI ulcers and bleeding.7,18 In 2010, an estimated 7,215 deaths were attributed to GI bleeds, one-third of which were blamed on NSAID use.19 Assessing the true GI risk of NSAIDs is difficult because they are commonly used inappropriately and/or in combination therapy. An estimated 12% of the general population uses NSAIDs regularly (at least 3 times per week for more than 3 months). A separate survey found that roughly 40% of respondents use both prescription and OTC NSAIDS, and that 29% believe OTC NSAIDs are safer than prescription NSAIDs.3,5,20 These NSAID usage patterns and perceptions are important because nearly 30% of GI bleeds are associated with aspirin use alone. The risk of bleeding can increase significantly for the estimated 16% of the population using NSAIDs and aspirin together.21 Clinicians should counsel patients to avoid concomitant use of prescription and OTC NSAIDs/aspirin, and should provide strategies for GI protection, if appropriate. At higher doses, all NSAIDs lose selectivity as they significantly inhibit both COX-1 and COX-2 and dramatically increase the risk of adverse effects, as demonstrated in the study that prompted the FDA’s 2015 NSAID class warnings on CV risk (Figure 2, page 62).22

Chemical Classes of Nonsteroidal Anti-Inflammatory Drugs


Figure 2. Relative Selectivity of NSAIDs as Inhibitors of COX-1 and COX-2 by Chemical Class
Cardiovascular Adverse Effects

It is important to recognize that NSAIDs are exclusively used for their antipyretic, analgesic, and anti-inflammatory properties, all of which are mediated by COX-2. That means NSAIDs (other than aspirin) are not used clinically for their COX-1-binding properties. Theoretically, NSAIDs with COX-2 > COX-1 inhibition will have an increased analgesic benefit while minimizing the bleeding risk. However, the FDA took the 2 most potent COX-2 selective inhibitors, rofecoxib (Vioxx) and valdecoxib (Bextra), off the market due to the increased risk of serious and potentially fatal CV thrombotic events, as well as rare toxic skin reactions.23,24

Recent studies, though, suggest we may have learned the wrong lessons from these earlier studies. The PRECISION trial compared moderate doses of celecoxib (Celebrex) with naproxen and ibuprofen in patients at risk for cardio-vascular disease in a randomized, double-blind, placebo-controlled trial. Unlike in previous COX-2 trials, clinicians more accurately reflected current practice by allowing patients to continue taking medications like aspirin for CV protection. In the trial, celecoxib was non-inferior to both naproxen and ibuprofen; patients had more CV events in the latter 2 treatment groups.25

A separate meta-analysis suggested that rofecoxib’s original clinical trial results significantly skewed the data and exaggerated the potential for CV events with other COX-2 selective NSAIDs (coxibs). When rofecoxib was removed from the coxib comparison group, none of the ensuing comparisons showed any difference in CV events, indicating that those COX-2 selective NSAIDs did not increase CV risk compared to traditional NSAIDs.26 These results suggest that some COX-2 selectivity is preferable. We recommend using the lowest dose of any NSAID, however, to decrease the risk of adverse effects.

Non-NSAID Alternatives


Acetaminophen (APAP) is generally regarded as a weak anti-inflammatory used mainly for the antipyretic and analgesic effects mediated by its inhibition of prostaglandin E2 (PGE2) generation within the central nervous system.27 In contrast to NSAIDs, acetaminophen does not inhibit the PGE2 or platelet-derived synthesis of inflammatory thromboxane A2, accounting for its minimal anti-inflammatory activity and lack of anti-platelet effects. Acetaminophen is regarded as safe in patients at risk for renal impairment and is not associated with CV thrombotic risk.28 For these reasons, acetaminophen is generally regarded as being relatively safe and well tolerated and is widely used as a first-line pain management option, despite evidence that NSAIDs have higher efficacy in a number of pain conditions.29

In general, acetaminophen and other pain relievers such as NSAIDs and opioids can have a synergistic and dose-sparing effect.28 Acetaminophen is not without risks, however. Due to the risk of hepatotoxicity caused by over-ingestion, acetaminophen is often combined with other prescription pain medications (including opioids) to deter overuse. Based on current research, doses up to 3,000 mg per day, or 4,000 mg per day under supervision, are considered safe. However, taking more than 4,000 mg per day, either as 1 large dose or excessive doses over weeks or months, may cause liver damage.30 Acetaminophen is widely available in OTC single-ingredient formulations and combination products for various ailments, including cold, cough, allergy, and pain, raising the risk that patients will take multiple acetaminophen-containing products that lead to hepatotoxicity.

Acetaminophen overdose, whether intentional or not, is the most common cause of acute liver failure in the United States.31 In 2011, the FDA mandated the inclusion of a boxed warning that highlighted the potential for severe liver injury. The agency also requested that drug manufacturers limit the amount of acetaminophen to 325 mg per dosage unit in combination with prescription medications, primarily opioids such as oxycodone, hydrocodone, and codeine.32 The FDA issued a separate Drug Safety Communication in 2013 that warned of rare but serious skin reactions associated with acetaminophen use, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, all of which can be fatal.33 Due to the varied risks associated with overuse, clinicians should counsel their patients to limit total daily consumption of acetaminophen from all sources.

Topical Agents

Topical analgesics offer some significant advantages, including quick onset of action and effectiveness for localized pain complaints, minimal systemic exposure, and lower risk of adverse effects compared to oral alternatives. Topicals should be considered particularly in vulnerable populations where oral agents may represent increased risk (ie, in elderly or pediatric patients or those with GI or CV risk). Topicals carry some disadvantages as well, which generally include higher costs (particularly if compounded), variable depth of penetration, potential for inaccurate dosing, oleaginous feeling, and necessity of repeated applications.

Salicylate-Containing Rubefacients

Salicylate-containing rubefacients cause skin irritation and are believed to relieve musculoskeletal pain in muscles, joints, tendons, and extremities through a counter-irritation mechanism. Irritation of sensory nerve endings alters or offsets pain in the underlying muscles or joints served by the same nerves.34 When applied topically, menthol (peppermint oil) dilates blood vessels and causes a cooling sensation and analgesic effect. Topical application of methyl salicylate (wintergreen oil) induces skin redness and irritation, yielding an analgesic effect. In the skin, methyl salicylate is converted to salicylate, a derivative of salicylic acid pharmacologically related to aspirin and NSAIDs.

A 2014 Cochrane meta-analysis determined that topically applied salicylates have very low relative risk as pain treatment options and are very well tolerated by adult patients. Only about 20% of methyl salicylate may be absorbed by the skin, however, leading to very low systemic levels of salicylate.35 Available evidence does not support the use of topical rubefacients containing salicylates for acute injuries or for chronic musculoskeletal pain conditions.36

Topical NSAIDs

In the United States, diclofenac is the only FDA-approved topical NSAID. It is available as a 1% gel (Voltaren), as a 1.5% to 2% solution (Pennsaid), and as a 1.3% patch (Flector). There are, however, numerous topical NSAIDs products that have been used clinically in Europe for nearly 30 years. Ibuprofen, ketoprofen, piroxicam, and indomethacin are commonly compounded NSAIDs, though they have not been studied as extensively as diclofenac and are not FDA approved for topical use.

Similar to systemic NSAIDs, topical NSAIDs reversibly inhibit COX, mediating production of prostaglandins and thromboxane A2. Topical application is based on the ability of NSAIDs to inhibit COX enzymes locally and peripherally, with minimal systemic uptake.

Compared with oral administration, topical administration leads to significantly higher tissue concentrations, potentially increasing the efficacy of treating localized musculoskeletal pain.32 In comparison with opioids, injectables, and corticosteroids, topical NSAIDs have the lowest number needed to treat (NNT = 3) for 1 hip or knee osteoarthritis patient to benefit (Table 1).37 In contrast, plasma drug concentrations after topical administration generally remain below 10% of those achieved after oral administration of NSAIDs.38

Despite having significantly lower systemic exposure than oral NSAIDs, topical diclofenac products have the same boxed warnings for CV and GI risk. No safety studies have lasted longer than 12 weeks in at-risk patients, however, and no trials have compared topical diclofenac with oral NSAIDs in high-risk patients. Based on the evidence, topical NSAIDs may be an important treatment modality for patients with localized pain who are not candidates for oral NSAID therapy.


Capsaicin, the pungent component of hot chili pepper, is a transient receptor potential vanilloid 1 (TRPV1) receptor agonist. TRPV1 is an ion channel-receptor complex expressed on nociceptive fibers in the skin that detect noxious painful stimuli. Initially, topical administration of capsaicin causes an enhanced stimulation of TRPV1-expressing cutaneous nociceptors that may be associated with painful sensations. Eventual analgesia is mediated by the death of distal nerve branches and the reduction in TRPV1-expressing nociceptive nerve endings. This is typically achieved only by regular application.34

Table 1. Relative Effect Size of Interventions  For Osteoarthritis of the Knee

Capsaicin is available in a variety of OTC preparations (Zostrin, Capsagel, Bengay, etc) and is indicated for temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, strains, bruises, and sprains. Several guidelines support using capsaicin for pain. The American Academy of Neurology (AAN), for example, considers it a second-line treatment for postherpetic neuralgia with level B evidence of effectiveness for painful diabetic neuropathy.39 The European Federation of Neurological Societies (EFNS) recommends capsaicin as a second- or third-line option for managing postherpetic neuralgia.40 Qutenza, a prescription-only capsaicin 8% patch, is FDA approved for managing neuropathic pain associated with postherpetic neuralgia.41 The International Association for the Study of Pain (IASP), meanwhile, recommends the patch as a second-line option for peripheral neuropathic pain syndromes.42


Lidocaine is an amide-type local anesthetic that inhibits the ionic fluxes required for impulse initiation and conduction.43 Stabilization of overactive nerves can be particularly useful for treating localized neuropathic pain. Topical lidocaine can be obtained OTC (Xylocaine, Aspercreme, etc) and via prescription (Emla) in a variety of preparations and concentrations. Lidocaine ointment is indicated for temporary relief of pain associated with minor burns, such as sunburns, abrasions of the skin, and insect bites. In comparison, the prescription-only lidocaine 5% patch (Lidoderm) is FDA approved for relief of pain associated with postherpetic neuralgia.

No trials have compared lidocaine cream/ointment formulations with the lidocaine 5% patch. Therefore, consensus recommendations for treating peripheral neuropathic pain haven’t deemed non-patch lidocaine alternatives to be therapeutic options.43 The AAN and the EFNS recommend the lidocaine patch as a first-line therapy for postherpetic neuralgia.39,44 The IASP and the Canadian Pain Society recommend the patch as a second-line and fourth-line option, respectively, for “mixed neuropathies” like diabetic peripheral neuropathy.42,45 Because topically administered lidocaine is approximately 70% bound to plasma proteins and has very low systemic exposure after its application, the risk of either systemic adverse events or pharmacokinetic interactions with concomitant medications is minimal.46


Recent prescribing guidelines, including those by the Centers for Disease Control and Prevention (CDC), recommend that clinicians utilize nonopioid therapies when possible. NSAIDs have proven efficacy for treating patients in pain and can decrease stiffness and inflammation and improve mobility. These are key aspects to the physical and functional rehabilitation strategies central to chronic pain management.

Other alternatives, such as acetaminophen and topical medications, can be highly effective in augmenting regimens or in targeting localized pain generators. Adjunct medication options should be selected for their ability to target underlying pain mechanisms, which often results in a decreased need for opioids. It is incumbent on clinicians serving those in persistent pain to develop expertise in adjunct pain medication management to ensure evidence-based and individualized care that improves outcomes for our patients.

Last updated on: April 29, 2019
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