An oral nonopioid analgesic is often sufficient for acute treatment of mild to moderate migraine pain without severe nausea or vomiting. A triptan is the drug of choice for treatment of moderate to severe migraine in most patients without vascular disease. Treatment of pain when it is still mild to moderate in intensity improves headache response and reduces the risk of recurrence.

Nonopioid drugs can be used in the treatment of many nociceptive and neuropathic pain conditions. For severe pain, especially severe chronic cancer pain, use of opioids may be necessary. Noninvasive nonpharmacologic treatments, including physical and psychological therapies, have been shown to improve pain and function in patients with some common chronic pain conditions and are unlikely to cause serious harms. A multimodal approach to analgesic therapy can increase pain control while reducing opioid use and adverse effects.

View the Comparison Table: Some Nonopioid Analgesics for Pain

Rheumatoid arthritis (RA) is prevalent in 0.5% of adults in the US; it is about 2.5 times more common in women than in men. Guidelines for treatment of RA from the American College of Rheumatology were recently updated. The goal of treatment is to minimize disease activity and prevent irreversible joint damage.

An oral nonopioid analgesic is often sufficient for acute treatment of mild to moderate migraine headache without severe nausea or vomiting. A triptan is the drug of choice for treatment of moderate to severe migraine headache pain in most patients without vascular disease. Early treatment of pain when it is still mild to moderate in intensity improves headache response and reduces the risk of recurrence.

Many different drugs are used for treatment of osteoarthritis pain, but none of them prevent progression of the disease. Nonpharmacologic approaches including weight management, exercise, tai chi, physical therapy, assistive devices, and total joint arthroplasty can also be used. The American College of Rheumatology (ACR) has published new guidelines for the management of osteoarthritis of the hip, hand, and knee.

Lasmiditan (Reyvow – Lilly), an oral serotonin (5-HT_1F) receptor agonist, and ubrogepant (Ubrelvy – Allergan), an oral calcitonin gene-related peptide (CGRP) receptor antagonist, have been approved by the FDA for acute treatment of migraine with or without aura in adults.

The FDA has approved a single-injection hyaluronic acid gel (Durolane – Bioventus) and an extended-release (ER) formulation of the synthetic corticosteroid triamcinolone acetonide (Zilretta – Flexion) for intra-articular (IA) treatment of osteoarthritic knee pain.

Disease-modifying antirheumatic drugs (DMARDs) are used for initial treatment of rheumatoid arthritis (RA) to achieve clinical remission and prevent irreversible joint damage (see Table 1). DMARDs generally do not have an immediate analgesic effect, but over time they can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Trexall, and others) is generally the drug of choice; it can be used for patients with low, moderate, or high disease activity. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

Nonopioid drugs can be used in the treatment of many nociceptive and neuropathic pain conditions. Use of opioids for pain will be reviewed in a future issue.

View the Comparison Table: Some Nonopioid Analgesics for Pain

Gastroesophageal reflux disease (GERD) is the most frequent GI condition encountered in the outpatient setting; it affects about 20% of the US population. Heartburn and regurgitation are the classic symptoms of GERD.

An oral nonopioid analgesic may be sufficient for treatment of mild to moderate migraine without severe nausea or vomiting. A triptan is the drug of choice for treatment of moderate to severe migraine. Use of a triptan early in an attack when pain is still mild to moderate in intensity improves headache response and reduces recurrence rates.

The FDA has approved a 10% nanoemulsion gel formulation of the porphyrin-based photosensitizer aminolevulinic acid hydrochloride (ALA; Ameluz – Biofrontera) for use in combination with a narrowband red light photodynamic therapy (PDT) lamp (BF-RhodoLED) for treatment of actinic keratoses (AKs) of mild to moderate severity on the face and scalp. A 20% ALA solution (Levulan Kerastick) approved for use in combination with blue light PDT (BLU-U) has been available in the US since 2002.

The FDA has approved Vivlodex (Iroko), a low-dose formulation of the nonsteroidal anti-inflammatory drug meloxicam (Mobic, and generics), for management of osteoarthritis pain. According to the manufacturer, the new formulation aligns with stronger FDA warnings about the cardiovascular risks of NSAIDs and the recommendation to use the lowest possible doses of these drugs.

The FDA has approved Dyloject (Hospira), an IV formulation of the NSAID diclofenac sodium, for use in adults. It can be administered alone for treatment of mild to moderate pain or in combination with opioid analgesics for moderate to severe pain. Dyloject is the first injectable formulation of diclofenac to become available in the US.

Psoriatic arthritis is a chronic inflammatory arthropathy that develops in up to 40% of patients with psoriasis. Several guidelines for treatment of psoriatic arthritis have been published.

For initial treatment of rheumatoid arthritis, most expert clinicians prescribe a disease-modifying antirheumatic drug (DMARD) and add a nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid to control symptoms. Methotrexate is generally the DMARD of choice...

DMARDs
Disease-modifying antirheumatic drugs (DMARDs) are used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Rheumatrex, and others) is generally the first DMARD prescribed; it can be used to treat mild, moderate, or severe RA. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

Many different drugs are used for treatment of osteoarthritis pain, but none of them prevent progression of the disease. Many nonpharmacologic approaches are available as well, including weight management, exercise, physical therapy, assistive devices, and total joint arthroplasty. New guidelines for the management of osteoarthritis have recently been published.

The same pharmaceutical company (Iroko) that recently marketed low-dose diclofenac (Zorvolex) for treatment of mild to moderate acute pain1 has now received approval from the FDA to market a low-dose oral formulation of indomethacin (Tivorbex) for the same indication. Tivorbex is available in 20- and 40-mg capsules; conventional immediate-release indomethacin capsules contain 25 mg and 50 mg of the drug.

The rationale for this new product is the same as the one offered for Zorvolex: the drug is formulated as submicron particles that increase surface area, leading to faster dissolution and absorption. According to the package insert, the time to reach peak serum concentrations (Tmax) was 1.67 hours with a 40-mg capsule of Tivorbex, compared to 2.02 hours with a standard 50-mg capsule of indomethacin.

The problem with Tivorbex is the same as the problem with Zorvolex: there are no studies comparing its efficacy to that of standard doses of indomethacin or to any other NSAID. In addition, indomethacin is generally considered one of the most potent NSAIDs and one of those most likely to cause GI bleeding, increase cardiovascular risk, and damage the kidneys. There is no good reason to use indomethacin in any dosage for treatment of mild to moderate pain.

1. Low-dose diclofenac (Zorvolex) for pain. Med Lett Drugs Ther 2014; 56:19.

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The FDA has approved Zorvolex (Iroko), a low-dose oral formulation of the relatively COX-2 selective NSAID diclofenac, for treatment of mild-to-moderate acute pain in adults.

Treatment of migraine in the emergency department, which may involve use of intravenous drugs, is not discussed here.

Pain can be acute or chronic. The two major types of chronic pain are nociceptive pain and neuropathic pain. Nociceptive pain can be treated with nonopioid analgesics or opioids. Neuropathic pain is less responsive to opioids and is often treated with adjuvant drugs such as antidepressants and antiepileptics. Combining different types of analgesics may provide an additive analgesic effect without increasing adverse effects.

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs (Table 1) generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. NSAIDs have immediate analgesic and antiinflammatory effects, but may not affect the disease process. Oral corticosteroids can relieve joint symptoms and control systemic manifestations, but their chronic use can cause many complications. Judicious use of intra-articular corticosteroids can rapidly decrease inflammation in acute joints with few, if any, adverse effects.

The FDA has approved ingenol mebutate (Picato – Leo) for topical treatment of actinic keratoses (AKs). The new drug is derived from the sap of the Euphorbia peplus plant, a traditional folk remedy for warts and other skin lesions.

Pain can be acute or chronic. Chronic pain has been broadly classified into two types: nociceptive and neuropathic. Nociceptive pain can be treated with nonopioid analgesics or opioids. Neuropathic pain is less responsive to opioids; adjuvant medicines such as antidepressants and anticonvulsants are often used to treat neuropathic pain. Combining different types of analgesics may provide an additive analgesic effect without increasing adverse effects.

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.

The nonsteroidal anti-inflammatory drug (NSAID) diclofenac, has been approved by the FDA in a 1% topical gel formulation (Voltaren Gel - Endo) for treatment of osteoarthritis (OA). A 3% topical diclofenac gel (Solaraze) is currently approved for treatment of actinic keratoses, but not for topical use on joints. No other topical NSAIDs are approved by the FDA for OA. A diclofenac patch (Flector) was recently approved by the FDA for treatment of pain due to minor strains, sprains and contusions.

Diclofenac epolamine patch 1.3% (Flector Patch - Alpharma), a topical formulation of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac, has been approved by the FDA for topical treatment of acute pain due to minor strains, sprains and contusions. It is the first topical NSAID patch approved in the US. A diclofenac patch has been used in Europe since 1993. Diclofenac sodium (Voltaren, and others) is available in the US as an oral tablet, in a 1% gel for treatment of osteoarthritis (to be reviewed in a future issue), in a 3% gel (Solaraze) for treatment of actinic keratoses, and in an ophthalmic formulation.

Pain can be acute or chronic. Chronic pain has been broadly classified into two types: nociceptive and neuropathic. Nociceptive pain is generally treated with nonopioid analgesics and opioids. Antidepressants and anticonvulsants have been used to treat neuropathic pain. Combining two different types of analgesics may nprovide an additive analgesic effect without increasing adverse effects.

To prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, disease modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA). The DMARDs listed in the table on page 84 have no immediate analgesic effects, but can control symptoms and have been shown to delay and possibly stop progression of the disease. The NSAIDs listed in the table on page 88 have analgesic and anti-inflammatory effects, but may not affect the disease process. Oral corticosteroids can rapidly relieve joint symptoms and control systemic manifestations, but their chronic use is associated with many complications.

At a US Senate hearing prompted by the withdrawal of Vioxx, an FDA officer cited 5 drugs as potentially dangerous. It may be useful to revisit Medical Letter reviews of these drugs.

With the removal of Vioxx from the market and concerns about cardiovascular toxicity with other selective COX-2 inhibitors, patients are looking for safe alternatives, and manufacturers of other drugs are looking for additional market share. The COX-2 inhibitors first became popular because they have less upper GI toxicity than older less selective NSAIDs, at least in the short term, in patients not taking aspirin.

Rofecoxib (Vioxx - Merck) has been withdrawn from the market due to an increased risk of cardiovascular complications associated with its long-term use. The question remains whether all selective COX-2 inhibitors carry the same risk. Full-page advertisements in newspapers for celecoxib (Celebrex - Pfizer), the most widely used COX-2 inhibitor, assure the public that it does not.

Low-dose aspirin is widely used as an antiplatelet drug to reduce the risk of cardiovascular disease (Medical Letter 2000; 42:18). Recent reports suggest that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (Motrin, and others) may decrease the efficacy of aspirin for this indication. The manufacturer of Tylenol is capitalizing on these reports by advertising that aspirin-taking patients who need pain relief should use acetaminophen instead of ibuprofen.

Three types of analgesic drugs are available: non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; opioids; and adjuvant drugs that are not usually thought of as analgesics, such as antidepressants, which can act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. Combining two different types of analgesics may provide an additive analgesic effect without necessarily increasing adverse effects.

Imiquimod cream 5% (Aldara - 3M), an immune modifier previously approved for treatment of genital and perianal warts (Medical Letter 1997; 39:118), has now been approved by the FDA for treatment of actinic keratoses (AKs) on the face or scalp, and may also be approved soon for treatment of basal cell carcinoma. It produces apoptosis in malignant, but not normal, human keratinocytes (M Sch÷n et al, J Natl Cancer Inst 2003; 95:1138).

Changes caused by one drug in the absorption, distribution, metabolism or excretion of another may lead to a pharmacokinetic adverse drug interaction (DN Juurlink et al, JAMA 2003; 289:1652). Additive drug interactions, such as vasodilation caused by both sildenafil (Viagra) and nitrates, can also have adverse effects.

Many different drugs are now used to treat rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs), listed in the table on page 26, have analgesic and anti-inflammatory effects, but may not affect the disease process. Corticosteroids can provide rapid relief of joint symptoms and control of systemic manifestations, but chronic use is associated with many complications. The "disease-modifying" anti-rheumatic drugs (DMARDs), listed on page 29, have no immediate analgesic effects, but can control symptoms and may delay progression of the disease (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, Arthritis Rheum 2002; 46:328). Interactions of anti-rheumatic drugs with other drugs are listed in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Several new treatments are now available for actinic keratoses (AKs), scaly pink papules commonly found on sun-exposed areas of the face, scalp, forearms and dorsal surface of the hands, particularly in the elderly. Some AKs regress spontaneously, but a few may progress to squamous cell carcinoma; the risk of progression has been estimated to be about 0.25% to 1% per year (EWB Jeffes III and EH Tang, Am J Clin Dermatol 2000; 1:167).

Related Articles Since Publication

Increasing use of rofecoxib (Vioxx) and celecoxib (Celebrex), both selective inhibitors of cyclooxygenase-2 (COX-2), for treatment of arthristis has been accompanied by concerns that they may increase risk of thrombotic cardiovascular events.

Three types of analgesic drugs are available: first, non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. Non-opioids can be given concurrently with opioids for an additive analgesic effect.

Pantoprazole, the fourth benzimidazole proton pump inhibitor to become available in the United States, has been marketed for short-term oral treatment of erosive gastroesophageal reflux disease (GERD).

Many different drugs are now used to treat rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic and anti-inflammatory effects, but may not affect the disease process. The "disease-modifying anti-rheumatic"drugs (DMARDs) have no immediate analgesic effects, but can control symptoms and may delay progression of the disease.

Meloxicam, a nonsteroidal anti-inflammatory drug (NSAID) with some cyclooxygenase-2 (COX-2) selectivity in vitro, has been approved by the FDA for treatment of osteoarthritis.

Rofecoxib, a selective COX-2 inhibitor, has been approved by the FDA for treatment of osteoarthritis, acute pain and menstrual pain.

Reports of adverse interactions between drugs continue to accumulate. Recently, the FDA has expanded the recommendations on drug interactions found in the package inserts of new drugs.

Celecoxib, a selective COX-2 inhibitor, has been approved by the FDA for treatment of osteoarthritis and rheumatoid arthritis.

Leflunomide (Arava - Hoechst Marion Roussel), which inhibits pyrimidine synthesis, and etanercept (Enbrel - Immunex/Wyeth-Ayerst), which blocks the action of tumor necrosis factor (TNF), have been approved by the FDA for treatment of rheumatoid arthritis. A third drug, infliximab (Remicade - Centocor), which also blocks TNF and has been used to treat rheumatoid arthritis, was approved earlier for treatment of Crohn's disease. Its use in Crohn's disease will be reviewed in a future issue.

Three types of analgesic drugs are available: first, non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, some drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain.

Ketorolac (kee' toe role ak) tromethamine 0.5%, a nonsteroidal anti-inflammatory drug (NSAID) previously available for parenteral and oral administration (Toradol - Medical Letter, 32:79, 1990), has now been approved for ophthalmic use (Acular - Allergan, Fisons) to relieve itching in seasonal allergic conjunctivitis. NSAIDs decrease prostaglandin concentrations in the eye, which theoretically might contribute to a decrease in itching. Several other NSAIDs are available for ophthalmic use in the USA, but none is marketed for this indication. Flurbiprofen (Ocufen) and suprofen (Profenal) are promoted for use in ophthalmic surgery to prevent miosis. Diclofenac (Voltaren) is available in an ophthalmic solution for treatment of post-operative inflammation after cataract extraction.

Oxaprozin (Daypro -Searle), a propionic acid-derivative nonsteroidal anti-inflammatory drug (NSAID), has been approved by the US Food and Drug Administration for once-daily treatment of rheumatoid arthritis and osteoarthritis. Some of the NSAIDs previously marketed in the USA are listed in the table on page 16. Ibuprofen, naproxen, fenoprofen, ketoprofen, and flurbiprofen are also propionic acid derivatives. Piroxicam and nabumetone (Medical Letter, 34:38, 1992) are also approved for once-daily use, and indomethacin is available in an extended-release formulation that can be taken once a day.

Nabumetone (Relafen - SmithKline Beecham), a new nonsteroidal anti-inflammatory drug (NSAID), has been approved by the US Food and Drug Administration for treatment of rheumatoid arthritis and osteoarthritis. The drug has been available in the United Kingdom since 1987. The manufacturer claims that nabumetone is as effective as other NSAIDs and causes a relatively low incidence of peptic ulcers.

Etodolac (Lodine - Wyeth-Ayerst), a nonsteroidal anti-inflammatory drug (NSAID) available in Europe for several years, was recently approved by the U.S. Food and Drug Administration for use in osteoarthritis and as a general-purpose analgesic. It has not been approved for treatment of rheumatoid arthritis.

Some commonly used systemic drugs that may cause pulmonary toxicity are listed in the table below. These adverse effects may sometimes be difficult to distinguish from the underlying disease (JAD Cooper, Jr et al, Am Rev Respir Dis, 133:321, 488, 1986). Pulmonary effects that are part of a generalized reaction or are indirect effects of drugs - on respiratory muscles, for example, or on the immune system - are not included here.

Diclofenac sodium (Voltaren - Geigy), a nonsteroidal anti-inflammatory drug (NSAID) available in some countries since 1974, was recently introduced in the USA for treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is being promoted as 'The number one prescribed antiarthritic in the world.'