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Introduction

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.

Conventional Nonopioid Analgesics

Acetaminophen

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 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

Salicylates

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.

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.

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.

Summary

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.

References

1. Munir MA, Enany N, Zhang JM. Nonopioid analgesics. Med Clin N Am. 2007;91(1):97-111.
2. Finnerup NB. Nonnarcotic methods of pain management. N Engl J Med. 2019;380(25):2440-2448.
3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.
4. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72(2):149-162.
5. Macfarlane GJ, Kronisch C, Atzeni F, et al. EULAR recommendations for management of fibromyalgia. Ann Rheum Dis. 2017;76(12):e54.
6. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(7):514-530.
7. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59(1):1-18.
8. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
9. Tauben D. Nonopioid medications for pain. Phys Med Rehabil Clin N Am. 2015;26(2):219-248.
10. Gabay M, Tanzi M. Medications for chronic pain – nonopioid analgesics. Practical Pain Management. 2011;11(3):1-9. https://www.practicalpainmanagement.com/treatments/pharmacological/non-opioids/medications-chronic-pain-nonopioid-analgesics. Accessed April 19, 2020.
11. Myers SH, LaPorte DM. Acetaminophen: safe use and associated risks. J Hand Surg Am. 2009;34(6):1137-1139.
12. Gerriets V, Nappe TM. Acetaminophen. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020.
13. Anon. Nonopioid drugs for pain. Med Lett Drugs Ther. 2018;60(1540):25-32.
14. Ofirmev [package insert]. Hazelwood, MO: Mallinckrodt Pharmaceuticals; 2018.
15. Facts & Comparisons [online database]. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc; 2020. https://fco.factsandcomparisons.com/lco/action/home. Accessed March 12, 2020.
16. Food and Drug Administration. FDA drug safety communication: prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. January 13, 2011. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit. Accessed April 19, 2020.
17. Food and Drug Administration. FDA drug safety communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen. August 1, 2013. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-serious-skin-reactions-pain-relieverfever-reducer. Accessed April 19, 2020.
18. Food and Drug Administration. FDA drug safety communication: FDA has reviewed possible risks of pain medicine use during pregnancy. January 9, 2015. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-has-reviewed-possible-risks-pain-medicine-use-during-pregnancy. Accessed April 19, 2020.
19. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320.
20. Celebrex [package insert]. New York, NY: Pfizer; 2019.
21. Abramson SB. Aspirin: mechanism of action, major toxicities, and use in rheumatic diseases. Last updated: May 8, 2019. www.uptodate.com. Accessed April 19, 2020.
22. Clinical Pharmacology [online database]. Tampa, FL: Elsevier; 2020. https://www.clinicalkey.com/pharmacology/?kbmRecipientKyCd=K52318174&keyCode=16n14255. Accessed March 12, 2020.
23. Krueger C. Medications for chronic pain – other agents. Practical Pain Management. 2011;11(5):1-12. https://www.practicalpainmanagement.com/treatments/pharmacological/medications-chronic-pain-other-agents. Accessed March 12, 2020.
24. Food and Drug Administration. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR). December 19, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin. Accessed April 19, 2020.
25. Lidoderm [package insert]. Malvern, PA: Endo Pharmaceuticals, Inc; 2018.
26. Qutenza [package insert]. Morristown, NJ: Averitas Pharma; 2018.
27. Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28(6):491-496.
28. Bastiaens L, Galus J, Mazur C. Abuse of gabapentin is associated with opioid addiction. Psychiatr Q. 2016;87(4):763-767.
29. Schjerning O, Rosenzweig M, Pottegard A, Damkier P, Nielsen J. Abuse potential of pregabalin. CNS Drugs. 2016;30(1):9-25.
30. Centers for Disease Control and Prevention. Nonopioid treatments for chronic pain. April 27, 2016. https://www.cdc.gov/drugoverdose/pdf/nonopioid_treatments-a.pdf. Accessed April 19, 2020.
31. Food and Drug Administration. A guide to safe use of pain medicine. February 9, 2009. https://www.fda.gov/consumers/consumer-updates/guide-safe-use-pain-medicine. Accessed April 19, 2020.

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