The Medical Letter® on Drugs and Therapeutics

Volume 60 February 12, 2018

IN THIS ISSUE ISSUEISSUE No. Nonopioid Drugs for ...... p 25 14331540 Comparison Table: Some Nonopioid for Pain ...... online Volume 56

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Published by The Medical Letter, Inc. • A Nonprofi t Organization • medicalletter.org The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: 800-211-2769 The Medical Letter® on Drugs and Therapeutics

Volume 60 February 12, 2018

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ISSUE IN THIS ISSUE ISSUE No. 14331540 Nonopioid Drugs for Pain Volume 56

TABLES IN THIS ISSUE Recommendations for Treatment of Pain Some Nonopioid Analgesics for Pain ...... p 26-27 Acute Pain Some Adjuvant Pain ...... p 30 ▶ For initial treatment of mild to moderate acute pain, nonopioid Comparison Table: Some Nonopioid Analgesics for Pain ...... online analgesics such as , acetaminophen, and NSAIDs are preferred. ▶ For localized pain, topical agents, including topical , Nonopioid drugs can be used in the treatment of many , and , can be used alone or as adjunctive treatment. nociceptive and conditions. Use of ▶ For moderate acute pain, most NSAIDs are more effective than for pain will be reviewed in a future issue. aspirin or acetaminophen and some have equal or greater effi cacy compared to oral opioids combined with acetaminophen or even injected opioids. NONOPIOID ANALGESICS ▶ For moderate to severe acute pain, a combination of an NSAID and acetaminophen may be as effective as an /acetaminophen Nonopioid analgesics, unlike full opioid agonists, have combination. a dose ceiling on their effect.1 ▶ For severe acute pain, immediate-release formulations of full opioid agonists are the drugs of choice. ACETAMINOPHEN — Acetaminophen has no clinically Chronic Noncancer Pain signifi cant anti-inflammatory activity. It is less ▶ Nonpharmacologic therapy and nonopioid pharmacologic therapy are recommended for treatment of chronic noncancer pain. effective than full doses of NSAIDs in relieving pain, ▶ Nonpharmacologic therapies that have shown effi cacy for but has fewer adverse effects. It is available in multiple treatment of include structured education and exercise programs, cognitive behavioral therapy, acupuncture, oral formulations, often in combination with other meditation, and massage. over-the-counter (OTC) or prescription drugs, and in ▶ NSAIDs are more effective than acetaminophen, but long-term use 2 can result in serious adverse effects including gastrointestinal, rectal and intravenous formulations. renal, and cardiovascular toxicity. ▶ For severe chronic pain that has not responded to other agents, Adverse Effects – Most healthy patients can take up to 4 use of opioids may be necessary. grams of acetaminophen daily with no adverse effects,3 Chronic but repeated use of such doses has been associated ▶ Full opioid agonists are generally the drugs of choice for severe with alanine aminotransferase (ALT) elevations.4 A chronic cancer pain. Neuropathic Pain dosage of 1 gram three times daily for 2 weeks has ▶ For initial treatment of neuropathic pain, an or an been shown to increase blood pressure slightly in antiepileptic can be used. patients with cardiovascular .5 Acetaminophen ▶ Topical agents such as lidocaine and capsaicin can be used for localized neuropathic pain. overdose can cause serious or fatal hepatotoxicity. In ▶ Combining an antidepressant and an antiepileptic may produce a some patients, such as those who are fasting, are heavy synergistic analgesic effect in neuropathic pain syndromes. users, or are concurrently taking isoniazid ▶ For severe pain that has not responded to other agents, use of opioids may be necessary. (INH), zidovudine (Retrovir, and others), or a barbiturate, hepatotoxicity can develop after moderate overdosage SALICYLATES — Aspirin is effective for most types or even with high therapeutic doses. Continued use of of mild to moderate pain, but it is now used mainly in acetaminophen may increase the anticoagulant effect low doses as a platelet inhibitor. Unlike other NSAIDs, of warfarin (Coumadin, and others) in some patients.6 a single dose of aspirin irreversibly inhibits platelet Some meta-analyses of cohort and case-control studies function for the 8- to 10-day life of the platelet, inter- have suggested that long-term use of acetaminophen fering with hemostasis and prolonging bleeding time. may increase the risk of developing renal cell cancer.7 Adverse Effects – A single dose of aspirin can Pregnancy – Occasional use of oral acetaminophen precipitate asthma symptoms in aspirin-sensitive during pregnancy is generally considered safe. patients. High doses or chronic use of aspirin can

25 Published by The Medical Letter, Inc. • A Nonprofi t Organization • medicalletter.org ® The Medical Letter Vol. 60 (1540) February 12, 2018

Table 1. Some Nonopioid Analgesics for Pain Some Available Usual Adult Drug Formulations Analgesic Dosage1 Comments Cost2 Acetaminophen3 – generic 325, 500 mg tabs4 650 mg q4-6h or 1000 mg q6-8h Less effective than full $1.305 Tylenol (McNeil Consumer) (max 4000 mg/d) doses of NSAIDs 4.205 Amount in prescription combination products limited to 325 mg/dosage unit Ofi rmev (Mallinckrodt) 10 mg/mL IV soln <50 kg: 15 mg/kg q6h or 12.5 mg/kg 112.606,7 q4h (max 75 mg/kg/d) ≥50 kg: 1000 mg q6h or 650 mg q4h (max 4000 mg/d) Salicylates Aspirin – generic 325 mg tabs, 500 mg 325-650 mg q4-6h (max 4000 mg/d) 0.305 Bayer (Bayer) caplets4,8 1.705 – generic 500 mg tabs 500 mg q8-12h (max 1500 mg/d) 500 mg comparable to 650 mg 79.00 of acetaminophen or aspirin with slower onset and longer duration – generic 500, 750 mg tabs 500 mg q6h or 1000 mg q12h 33.30 (max 3000 mg/d) Some Nonselective NSAIDs Diclofenac9 – generic 50 mg tabs 50 mg q8-12h (max 200 mg/d) Comparable to aspirin with 14.60 longer duration Dyloject (Hospira) 37.5 mg/mL single- 37.5 mg IV q6h (max 150 mg/d) Also available in a fi xed- 63.007 dose vials dose combination with Zipsor (Depomed) 25 mg caps 25 mg qid (max 200 mg/d) misoprostol (Arthrotec) 303.40 Zorvolex (Iroko) 18, 35 mg caps 18 or 35 mg tid to decrease GI toxicity 81.70 – generic 200, 300 mg caps; 200-400 mg q6-8h (max 1000 mg/d)10 200 mg comparable to 4.90 400, 500 mg tabs 400 mg; possibly extended-release – generic11 400, 500, 600 mg 400-1000 mg once/d superior to aspirin 650 mg 16.20 ER tabs – generic 200, 400 mg caps; 200 mg q4-6h (max 3200 mg/d)12 333.50 600 mg tabs Nalfon (Xspire) 400 mg caps 96.2013 Flurbiprofen11 – generic 50, 100 mg tabs 100 mg q12h (max 300 mg/d) 5.90 Ibuprofen – generic 400, 600, 800 mg tabs 400 mg q4-6h (max 2400 mg/d) 200 mg equal to 650 mg of 3.80 aspirin or acetaminophen; 400 mg comparable to acetaminophen/ Also available in a fi xed-dose combination with famotidine (Duexis) to decrease GI toxicity Caldolor (Cumberland) 100 mg/mL IV soln 400-800 mg IV q6h (max 3200 mg/d) Modest opioid-sparing effect 29.407 Effectiveness compared to IV unclear Ibuprofen OTC – generic 100, 200 mg tabs; 200-400 mg q4-6h 200 mg equal to 650 mg of 1.105 Advil (Pfi zer Consumer) 200 mg caps (max 1200 mg/d) aspirin or acetaminophen 2.205 ER = extended-release 1. Dosage adjustment may be needed for renal or hepatic impairment. 2. Approximate WAC for one week of treatment with the lowest dose and/or longest dosing interval. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. January 5, 2018. Reprinted with permission by First Databank, Inc. All rights reserved. ©2018. www.fdbhealth.com/policies/drug-pricing-policy. 3. Acetaminophen is included in multiple prescription and OTC products for treatment of pain, cough, cold, flu, migraine, insomnia, etc., increasing the risk for accidental overdosage. 4. Also available in other strengths and dosage forms, alone and in combination with other drugs, both OTC and by prescription. 5. Cost at www.walgreens.com. Accessed February 1, 2018. 6. Cost based on treatment of a 70-kg patient. 7. Cost for one day of treatment at the lowest dosage. 8. Also available in chewable, buffered, enteric-coated, and extended-release formulations. 9. Also available in enteric-coated and extended-release tabs for use in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as a topical patch (Flec- tor) for treatment of pain due to minor strains, sprains, and contusions, as a topical gel (Voltaren 1% Gel) for use in ostearthritis, and as a topical solution (Pennsaid 2%) for use in osteoarthritis of the knee. 10. For use in osteoarthritis or rheumatoid arthritis the dosage is 300 mg bid or tid, 400 mg bid, or 500 mg bid. cause gastrointestinal (GI) ulceration and salicylate Nonacetylated salicylates such as diflunisal and intoxication. Taking buffered or enteric-coated salsalate do not interfere with platelet aggregation, formulations can reduce GI upset but not the risk of GI are rarely associated with GI bleeding, and are well ulceration, and could delay pain relief. Aspirin should tolerated by asthmatic patients, but there are no not be used during viral syndromes in children and controlled trials demonstrating their comparative teenagers because of the risk of Reye’s syndrome. effi cacy for treatment of chronic pain.

26 ® The Medical Letter Vol. 60 (1540) February 12, 2018

Table 1. Some Nonopioid Analgesics for Pain (continued) Some Available Usual Adult Drug Formulations Analgesic Dosage1 Comments Cost2 – generic 50, 75 mg caps 50 mg q6h or 75 mg q8h 25 mg comparable to ibuprofen $14.10 (max 300 mg/d) 400 mg and superior to aspirin extended-release – generic 200 mg ER caps 200 mg once/d 650 mg; 50 mg superior to 60.60 acetaminophen/codeine combination Ketorolac – generic 10 mg tabs 10 mg q4-6h (max 40 mg/d)14 10 mg comparable to ibuprofen 28.5015 400 or 800 mg or 500- 550 mg 15 mg/mL, 30 mg/mL, <65 yrs: 30 mg IM or IV q6h Comparable to 12 mg IM 30.2017 60 mg/2 mL injection (max 120 mg/d)16 with longer >65 yrs: 15 mg IM or IV q6h duration (max 60 mg/d)16 Sprix (Egalet) 15.75 mg/intranasal spray <65 yrs: 1 spray q6-8h in each nostril 1625.7019 (max 126 mg/d)18 >65 yrs: 1 spray q6-8h in one nostril (max 63 mg/d)18 Meclofenamate – generic 50, 100 mg caps 50-100 mg q4h (max 400 mg/d) 140.10 – generic 250 mg caps 500 mg once, then 250 mg q6h20 Comparable to aspirin but more 93.20 (max 1250 mg d 1, then 1000 mg/d) effective in dysmenorrhea – generic11 7.5, 15 mg tabs; 7.5-15 mg once/d Appears to be more selective 0.70 7.5 mg/5mL PO susp for COX-2 than COX-1 at low Mobic (Boehringer 7.5, 15 mg tabs doses (7.5 mg) 54.70 Ingelheim)11 Vivlodex (Iroko)21 5, 10 mg caps 5 or 10 mg once/d 167.40 Nabumetone11 – generic 500, 750 mg tabs 500 or 750 mg q8-12h (max 2000 mg/d) 16.10 Naproxen – generic 250, 375, 500 mg tabs; 250 mg q6-8h or 500 mg q12h 250 mg probably comparable 2.30 375, 500 mg enteric-coated (max 1250 mg d 1, then 1000 mg/d) to aspirin 650 mg with longer tabs; 25 mg/mL PO susp duration; 500 mg superior to Naprosyn, EC-Naprosyn 500 mg tabs; 375, 500 mg aspirin 650 mg 83.00 (Canton, Key) enteric-coated tabs; 25 mg/mL PO susp Naproxen sodium – generic 275, 550 mg tabs 275 mg q6-8h or 550 mg q12h 275 mg comparable to aspirin 10.50 Anaprox DS 550 mg tabs (max 1375 mg d 1, then 1100 mg/d) 650 mg with longer duration; 130.30 (Canton) 550 mg superior to aspirin 650 mg with longer duration Also available in a fi xed-dose combination with esomeprazole (Vimovo) to decrease GI toxicity Naproxen sodium OTC – generic 220 mg tabs 220 mg q8-12h (max 660 mg/d) 440 mg comparable to 400 mg 1.305 Aleve (Bayer) ibuprofen with longer duration 1.705 Selective COX-2 Inhibitor – generic 50, 100, 200, 400 mg caps 400 mg once, then 200 mg q12h Less effective than full doses 16.10 Celebrex (Pfi zer) (max 600 mg d 1, then 400 mg/d)22 of naproxen or ibuprofen 168.80 ER = extended-release 11. FDA-approved only for use in osteoarthritis and rheumatoid arthritis. 12. For use in osteoarthritis or rheumatoid arthritis, the dosage is 400-600 mg tid or qid. 13. Cost for one week of treatment with 400 mg tid. 14. Recommended only for continuation therapy after IM or IV ketorolac; total use of ketorolac not to exceed 5 days. 15. Cost of 5 days' treatment. 16. Use should be limited to 5 days because of GI toxicity; can also be given IM as a single 60 mg (<65 yrs) or 30 mg (≥65 years) dose. 17. Cost of 5 days' treatment for a <65-year-old patient. 18. Dose in patients weighing <50 kg or with renal impairment (GFR 30-90 mL/min) is one spray in one nostril; maximum 4 doses/day for up to 5 days. 19. Cost of one carton containing 5 single-day nasal spray bottles. 20. Duration of use usually not to exceed 1 week for acute pain or 2-3 days for dysmenorrhea. 21. FDA-approved only for use in osteoarthritis. 22. The dosage is 200 mg/d for use in osteoarthritis and 200-400 mg/d for use in rheumatoid arthritis.

NSAIDS — Single full doses of nonselective NSAIDs effi cacy to moderate doses of morphine in patients with such as ibuprofen or naproxen are more effective than acute pain. An IV formulation of diclofenac (Dyloject) full doses of acetaminophen or aspirin for treatment of may act more rapidly than IV ketorolac, but is otherwise acute pain.8 Some NSAIDs have an analgesic effect that similar in effi cacy.10 is equal to or greater than that of usual doses of an oral How NSAIDs compare to other analgesics for treatment opioid combined with acetaminophen.9 Intramuscular of chronic pain is less well established. Some patients or intravenous ketorolac is comparable in analgesic may respond better to one NSAID than another. The

27 ® The Medical Letter Vol. 60 (1540) February 12, 2018

COX-2-selective NSAID celecoxib is about as effective Renal Toxicity – All NSAIDs, including celecoxib, inhibit as a nonselective NSAID for treatment of osteoarthritis renal prostaglandins, decrease renal blood flow, cause and rheumatoid arthritis,11 but it is less effective for fluid retention, and may cause hypertension and renal treatment of acute pain, such as that following surgical failure, particularly in elderly patients. Diminished renal or dental procedures. function or decreased effective intravascular volume due to diuretic therapy, cirrhosis, or heart failure can Low-dose oral formulations of three NSAIDs, diclofenac increase the risk of NSAID-induced renal toxicity. (Zorvolex), indomethacin (Tivorbex), and meloxicam (Vivlodex), have been approved by the FDA for treatment Cardiovascular Effects – An increased risk of serious of mild to moderate acute pain and/or osteoarthritis cardiovascular events, including myocardial infarction, pain. They are formulated as submicron particles that stroke, and out-of-hospital cardiac arrest has been increase surface area, leading to faster dissolution and reported with some NSAIDs; the risk appears to be absorption. How they compare in effi cacy and safety to highest with diclofenac and lowest with naproxen.22-24 standard doses of the same drugs, which cost much In one randomized trial in patients with osteoarthritis less, is unknown.12-14 The potent NSAID indomethacin is or rheumatoid arthritis and cardiovascular risk associated with a high risk of adverse effects; it should factors, celecoxib was found to be noninferior to the not be used in any dosage for treatment of mild to nonselective NSAIDs ibuprofen and naproxen with moderate pain. regard to cardiovascular safety.25 However, the average Guidelines from the American College of Physicians dose of celecoxib (about 200 mg/day) was lower than recommend NSAIDs as fi rst-line options for patients the doses previously associated with cardiotoxicity. with chronic low who have an inadequate In addition, about 50% of the patients were taking response to nonpharmacologic treatment.15 Meta- low-dose aspirin at baseline; since ibuprofen and analyses of randomized trials in patients with chronic naproxen, but not celecoxib, inhibit aspirin binding to or spinal pain have found that NSAIDs platelet COX-1, the cardioprotective effects of aspirin reduce pain intensity and improve disability compared may have been blunted in patients who took ibuprofen to placebo; the effi cacy of different NSAIDs appeared or naproxen.26 to be similar in these patients.16,17 Other Effects – Like aspirin, nonaspirin NSAIDs can Bleeding – All NSAIDs, except celecoxib and, to precipitate asthma symptoms and anaphylactoid a lesser extent, meloxicam and , can reactions in aspirin-sensitive patients. They frequently interfere with platelet function and prolong bleeding cause small increases in aminotransferase levels; time. The NSAID-induced antiplatelet effect, unlike serious hepatotoxicity is rare, but may occur more that of aspirin, is reversible when the NSAID is cleared. frequently with diclofenac. Pancreatitis has been reported. Cholestatic hepatitis has occurred with GI Adverse Effects – Dyspepsia and GI ulceration, celecoxib, possibly related to sulfonamide allergy; perforation, and bleeding can occur with all NSAIDs, celecoxib is contraindicated in patients allergic to including parenteral formulations, often without sulfonamides. warning. High doses, prolonged use, previous peptic ulcer disease, concomitant systemic corticosteroids or NSAIDs can cause CNS adverse effects such as aspirin (even 81 mg/day), excessive alcohol intake, and dizziness, anxiety, drowsiness, confusion, depression, advanced age increase the risk of these complications. disorientation, severe , and aseptic Use of ketorolac is limited to 5 days because of its high meningitis. They have been associated with both risk of GI toxicity. Celecoxib appears to cause less GI mild and severe skin reactions, including exfoliative toxicity than nonselective NSAIDs.18 dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. NSAIDs rarely cause blood Taking an NSAID with a proton pump inhibitor such dyscrasias; aplastic anemia has been reported with as omeprazole (Prilosec OTC, and generics), an H2- ibuprofen, fenoprofen, naproxen, indomethacin, receptor antagonist such as ranitidine (Zantac, and , and . Long-term use of nonaspirin generics), or the prostaglandin analog misoprostol NSAIDs has been associated with an increased risk of ( Cytotec, and generics) may decrease the incidence of GI renal cell cancer.27 toxicity.19 Arthrotec (diclofenac/misoprostol), Vimovo (naproxen/esomeprazole), and Duexis (ibuprofen/ Pregnancy – Exposure to NSAIDs during pregnancy famotidine) are three commercially-available combi- or around the time of conception has been associated nations of an NSAID and a gastroprotective agent.20,21 with an increased risk of miscarriage, but the data

28 ® The Medical Letter Vol. 60 (1540) February 12, 2018 are weak. Use of NSAIDs during the third trimester , a serotonin and norepinephrine reuptake of pregnancy may cause premature closure of inhibitor (SNRI), has been reported to be effective in the ductus arteriosus and persistent pulmonary various types of neuropathic pain, including diabetic hypertension in the neonate, but these effects appear neuropathy, post-mastectomy pain syndrome, and to be uncommon if the drug is discontinued 6-8 chemotherapy-induced neurotoxicity, and has also been weeks before delivery. used to treat fi bromyalgia,30,31 but it is not FDA-approved for any of these indications. , another SNRI, Drug Interactions – NSAIDs can decrease the is FDA-approved for treatment of pain associated effectiveness of diuretics, beta blockers, ACE with diabetic peripheral neuropathy and fi bromyalgia, inhibitors, and some other antihypertensive drugs, and for chronic musculoskeletal pain.32-34 In patients and can increase serum concentrations of lithium and with chronic low back pain or osteoarthritis, it is only methotrexate, possibly resulting in toxicity. They may modestly more effective than placebo. Milnacipran, an increase the INR in patients taking warfarin. Patients SNRI approved by the FDA only for use in fi bromyalgia,35 taking aspirin for cardiovascular protection should not is moderately effective in decreasing pain and improving take ibuprofen or naproxen regularly because they can function. It inhibits norepinephrine reuptake to a greater interfere with aspirin’s antiplatelet effect. extent than it does serotonin reuptake. How it compares to venlafaxine or duloxetine is unclear. SNRIs can cause COMBINATION TREATMENT FOR ACUTE PAIN — A nausea, dizziness, increased sweating, tachycardia, combination of an NSAID and acetaminophen is , urinary retention, and a dose-dependent more effective than either drug alone and may be increase in blood pressure. Severe discontinuation an alternative to opioid analgesics for treatment of symptoms and sustained hypertension can occur with moderate to severe acute pain. In a double-blind trial, venlafaxine. Severe liver injury has been reported with 411 patients with moderate to severe acute extremity duloxetine and milnacipran. pain were randomized to treatment with single doses of one of four combination analgesic regimens There is no good evidence that selective serotonin (ibuprofen 400 mg plus acetaminophen 1000 mg or reuptake inhibitors (SSRIs) are effective for treatment either 5 mg, 5 mg, or codeine of neuropathic pain.36 30 mg plus acetaminophen 300-325 mg). There were no statistically signifi cant differences in pain reduction ANTIEPILEPTICS — In controlled trials, has between the nonopioid regimen and the opioid- been effective in reducing pain in postherpetic containing regimens at two hours after administration (an FDA-approved use) and diabetic neuropathy.37 of the drugs.28 Gabapentin can cause dizziness, somnolence, peripheral edema, and weight gain. , which ADJUVANT PAIN MEDICATIONS is similar in structure to gabapentin, is now available and antiepileptics are the mainstay of in a once-daily, extended-release formulation. treatment for a variety of neuropathic pain syndromes, Immediate-release and extended-release pregabalin including postherpetic neuralgia, diabetic neuropathy, are FDA-approved for treatment of postherpetic fi bromyalgia, complex regional pain syndrome, and neuralgia and diabetic peripheral neuropathy. The phantom limb pain, even though most of them are not immediate-release formulation is also approved for FDA-approved for these indications. fi bromyalgia (the extended-release formulation failed to show effi cacy in these patients).38,39 In a randomized, ANTIDEPRESSANTS — Tricyclic antidepressants double-blind, 8-week trial in 209 patients with acute or such as , nortriptyline, and imipramine chronic sciatica, pregabalin 150-600 mg daily did not can relieve many types of neuropathic pain, including signifi cantly reduce the intensity of leg pain compared diabetic neuropathy, postherpetic neuralgia, poly- to placebo.40 The dose of pregabalin can be titrated neuropathy, and nerve injury or infi ltration with cancer. more rapidly than that of gabapentin. Like gabapentin, They are also effective for treatment of fi bromyalgia it can cause dizziness, somnolence, and peripheral 29 pain. The analgesic effects of these drugs are edema; signifi cant weight gain has been reported in likely due to their inhibition of norepinephrine some patients. and serotonin reuptake. They commonly cause orthostatic hypotension, weight gain, sedation, sexual Use of higher-than-recommended doses of gaba- dysfunction, and anticholinergic effects (urinary pentin and pregabalin to achieve euphoric highs is retention, constipation, dry mouth, blurred vision, increasingly being reported; risk factors include a memory impairment, and confusion). history of substance abuse, particularly of opioids,

29 ® The Medical Letter Vol. 60 (1540) February 12, 2018

Table 2. Some Adjuvant Pain Medications1

Drug Some Available Formulations Usual Dosage for Pain2 Cost3 Tricyclic Antidepressants Amitriptyline – generic 10, 25, 50, 75, 100, 150 mg tabs 25-100 mg once/d $8.50 Imipramine HCl – generic 10, 25, 50 mg tabs 50-100 mg once/d or divided 15.40 Tofranil (Mallinckrodt) 613.20 Imipramine pamoate – generic 75, 100, 125, 150 mg caps 75-100 mg once/d 354.00 Nortriptyline – generic 10, 25, 50, 75 mg caps; 75 mg once/d or divided 13.50 10 mg/5 mL PO soln Pamelor (Mallinckrodt) 10, 25, 50, 75 mg caps 1249.60 Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine – generic 25, 37.5, 50, 75, 100 mg tabs 75 mg once/d-tid 10.70 extended-release – generic 37.5, 75, 150 tabs and caps; 225 mg tabs 75-150 mg once/d 15.70 Effexor XR (Pfi zer) 37.5, 75, 150 mg caps 422.20 Duloxetine – generic 20, 30, 60 mg delayed-release caps 60 mg once/d 19.30 Cymbalta (Lilly) 239.70 Milnacipran – Savella (Allergan) 12.5, 25, 50, 100 mg tabs 50 mg bid 348.80 Antiepileptics Gabapentin – generic 100, 300, 400 mg caps; 600, 800 mg tabs; 600-1200 mg tid 14.30 Neurontin (Pfi zer) 250 mg/5 mL PO soln 908.60 extended-release Gralise (Depomed) 300, 600 mg ER tabs 1800 mg once/d 695.00 Horizant (GlaxoSmithKline) 600 mg ER tabs 600 mg bid 777.00 Pregabalin – Lyrica (Pfi zer) 25, 50, 75, 100, 150, 200, 225, 75-300 mg bid or 445.00 300 mg caps; 20 mg/mL PO soln 50-200 mg tid extended-release – Lyrica CR 82.5, 165, 330 mg ER tabs 330-660 mg once/d 383.10 – generic 200 mg tabs; 100 mg chewable tabs; 200-400 mg bid 53.70 Tegretol (Novartis) 100 mg/5 mL PO susp 143.40 extended-release – generic 100, 200 mg ER caps and tabs; 200-400 mg bid 201.80 300 mg ER caps; 400 mg ER tabs Tegretol XR (Novartis) 100, 200, 400 mg ER tabs 153.20 Carbatrol (Shire) 100, 200, 300 mg ER caps 106.40 Equetro (Validus) 100, 200, 300 mg ER caps 217.90 Oxcarbazepine – generic 150, 300, 600 mg tabs; 300-600 mg bid 33.00 Trileptal (Novartis) 300 mg/5 mL PO susp 494.00 extended-release Oxtellar XR (Supernus) 150, 300, 600 mg ER tabs 600-2400 mg once/d 470.90 ER = extended-release 1. Some of the drugs listed here are not FDA-approved for treatment of pain. 2. Dosage may need to be adjusted for renal or hepatic impairment. 3. Approximate WAC for 30 days’ treatment at the lowest usual dosage and/or longest dosing interval. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. January 5, 2018. Reprinted with permission by First Databank, Inc. All rights reserved. ©2018. www.fdbhealth.com/policies/drug-pricing-policy. and the presence of psychiatric comorbidities.41,42 alone.44 However, in another study in patients with Pregabalin is a schedule V controlled substance. diabetic peripheral neuropathy, a combination of standard doses of pregabalin and duloxetine was not Carbamazepine is FDA-approved for treatment of signifi cantly different from high-dose monotherapy pain due to trigeminal neuralgia. Oxcarbazepine, with either drug alone.45 which is structurally related to carbamazepine, is not FDA-approved for treatment of pain. It has been In a study in patients with neuropathic pain, taking shown to be modestly effective in relieving peripheral lower doses of gabapentin and morphine together neuropathic pain, and may be better tolerated than provided better analgesia than taking either drug carbamazepine.43 alone.46 However, a population-based, case-control study found that opioid users taking moderate or high COMBINATION TREATMENT FOR NEUROPATHIC doses of gabapentin concomitantly had a signifi cantly PAIN — Combining an antidepressant and an increased risk of opioid-related death.47 antiepileptic may produce a synergistic analgesic effect in neuropathic pain syndromes, but clinical trials have OTHER DRUGS — (Prialt), a synthetic produced conflicting results. In one study in patients neuronal N-type , is with diabetic polyneuropathy or postherpetic neuralgia, administered intrathecally via a programmable a combination of gabapentin and nortriptyline was microinfusion device for treatment of severe chronic more effective than monotherapy with either drug pain. The drug has been effective, both as monotherapy

30 ® The Medical Letter Vol. 60 (1540) February 12, 2018 and when added to standard therapy, for treatment of of application. An 8% capsaicin patch (Qutenza) refractory severe chronic pain, including neuropathic is FDA-approved for treatment of postherpetic pain. Severe psychiatric effects (paranoid reactions, neuralgia.57 Application of the patch for one hour is psychosis) and CNS toxicity (confusion, somnolence, modestly effective in reducing pain associated with unresponsiveness) can occur. Use of a low starting postherpetic neuralgia for up to 3 months. The patch dose followed by titration in small increments once is applied during an offi ce visit; an increase in pain is weekly is recommended to increase tolerability.48,49 common during and for a few days after application. Unlike opioids, ziconotide does not cause tolerance, Topical diclofenac is available as a patch (Flector), dependence, or respiratory depression, and is not a a gel (Voltaren 1%) and a solution (Pennsaid 2%) for controlled substance.50 treatment of osteoarthritis or musculoskeletal pain.

Caffeine in doses of 65-200 mg may enhance the Topical analgesics containing , methylsalicy- analgesic effect of acetaminophen, aspirin, or late, or capsaicin are available OTC for treatment of mild ibuprofen in patients with acute pain.51 muscle and joint pain; while generally well-tolerated, given parenterally in doses of 25-50 mg may add to there have been rare reports of severe skin burns requir- the analgesic effect of opioids in postoperative and ing treatment or hospitalization.58 A 4% lidocaine patch cancer pain while reducing the incidence of nausea is also available OTC. and vomiting. Corticosteroids can produce analgesia NONPHARMACOLOGIC THERAPIES — Some non- in some patients with inflammatory or pharmacologic therapies that have shown effi cacy for tumor infi ltration of nerves. The oral and transdermal treatment of chronic pain include structured education patch formulations of the alpha -adrenergic agonist 2 and exercise programs, cognitive behavioral therapy, may improve pain and in acupuncture, meditation, and massage.59 Movement sympathetically maintained pain, but can cause therapies such as yoga, pilates, and tai chi may also be hypotension. Injections of botulinum toxin type A effective.60 A large review of clinical studies examining have been shown to be effective for treatment of exercise programs for various types of chronic pain postherpetic neuralgia, diabetic neuropathy, trigeminal found that these interventions are unlikely to cause neuralgia, and intractable neuropathic pain such as harm and may be associated with improvements poststroke pain and spinal cord injury.52 in pain severity and physical function.61 Guidelines and – Two oral prescription from the American College of Physicians recommend cannabinoids are available in the US. Dronabinol nonpharmacologic therapies as a fi rst-line option for (Marinol, and generics), a synthetic form of delta-9 treatment of low back pain.17 ■ (THC), and (Cesamet), a synthetic analog of THC, are both FDA-approved for Additional Content Available Online treatment of nausea and vomiting associated with cancer Comparison Table: Some Nonopioid Analgesics for Pain http://medicalletter.org/TML-article-1540b chemotherapy; dronabinol is also approved for anorexia in patients with AIDS. Use of cannabis and cannabinoids for treatment of pain remains controversial. Randomized 1. DE Becker et al. : Part 1: Managing acute and postoperative dental pain. Anesth Prog 2010; 57:67. trials of cannabinoids have found some evidence of 2. Intravenous acetaminophen (Ofi rmev). Med Lett Drugs Ther effi cacy for second-line treatment of cancer pain, 2011; 53:26. 3. Acetaminophen safety - Deja vu. Med Lett Drugs Ther 2009; neuropathic pain, and the spasticity of multiple sclerosis, 51:53. but none are currently approved by the FDA for these 4. PB Watkins et al. Aminotransferase elevations in healthy adults indications.53 Results of randomized controlled trials of receiving 4 grams of acetaminophen daily: a randomized con- trolled trial. JAMA 2006; 296:87. cannabis products, including , a standardized 5. In brief: Does acetaminophen increase blood pressure? Med cannabis extract available outside the US, suggest that Lett Drugs Ther 2011; 53:29. 6. Addendum: Warfarin-acetaminophen interaction. Med Lett cannabis may alleviate neuropathic pain over the short Drugs Ther 2008; 50:45. term in some patients; the effi cacy of cannabis for other 7. S Karami et al. Analgesic use and risk of renal cell carcinoma: a types of chronic pain remains to be established.54,55 case-control, cohort and meta-analytic assessment. Int J Can- cer 2016; 139:584. Topical Analgesics – A 5% lidocaine patch (Lidoderm) 8. JA Forbes et al. Evaluation of , aspirin, and ibuprofen in postoperative oral surgery pain. Pharmacotherapy 1991; 11:64. is FDA-approved for treatment of postherpetic 9. M Nauta et al. Codeine-acetaminophen versus nonsteroidal neuralgia.56 It is widely used off-label for other types anti-inflammatory drugs in the treatment of post-abdominal surgery pain: a systematic review of randomized trials. Am J of pain despite a lack of clinical trials supporting Surg 2009; 198:256. its effi cacy. Skin irritation can occur at the site

31 ® The Medical Letter Vol. 60 (1540) February 12, 2018

10. Intravenous diclofenac (Dyloject). Med Lett Drugs Ther 2015; 37. Gabapentin (Neurontin) for chronic pain. Med Lett Drugs Ther 57:171. 2004; 46:29. 11. PL McCormack. Celecoxib: a review of its use for symptomatic 38. Pregabalin (Lyrica) for neuropathic pain and epilepsy. Med relief in the treatment of osteoarthritis, rheumatoid arthritis and Lett Drugs Ther 2005; 47:75. ankylosing spondylitis. Drugs 2011; 71:2457. 39. W Häuser et al. Treatment of fi bromyalgia syndrome with 12. Low-dose diclofenac (Zorvolex) for pain. Med Lett Drugs Ther gabapentin and pregabalin—a meta-analysis of randomized 2014; 56:19. controlled trials. Pain 2009; 145:69. 13. In brief: Low-dose indomethacin (Tivorbex) for pain. Med Lett 40. S Mathieson et al. Trial of pregabalin for acute and chronic Drugs Ther 2014; 56:64. sciatica. N Engl J Med 2017; 376:1111. 14. Low-dose meloxicam (Vivlodex) for osteoarthritis pain. Med 41. KE Evoy et al. Abuse and misuse of pregabalin and gabapen- Lett Drugs Ther 2016; 58:35. tin. Drugs 2017; 77:403. 15. WT Enthoven et al. Non-steroidal anti-inflammatory drugs for 42. GC Quintero. Review about gabapentin misuse, interactions, chronic low back pain. Cochrane Database Syst Rev 2016; contraindications and side effects. J Exp Pharmacol 2017; 2:CD012087. 9:13. 16. GC Machado et al. Non-steroidal anti-inflammatory drugs 43. M Zhou et al. Oxcarbazepine for neuropathic pain. Cochrane for spinal pain: a systematic review and meta-analysis. Ann Database Syst Rev 2017; 12:CD007963. Rheum Dis 2017; 76:1269. 44. I Gilron et al. Nortriptyline and gabapentin, alone and in com- 17. A Qaseem et al. Noninvasive treatments for acute, subacute, bination for neuropathic pain: a double-blind, randomised and chronic low back pain: a clinical practice guideline from the controlled crossover trial. Lancet 2009; 374:1252. American College of Physicians. Ann Intern Med 2017; 166:514. 45. S Tesfaye et al. Duloxetine and pregabalin: high-dose mono- 18. FKL Chan et al. Gastrointestinal safety of celecoxib versus therapy or their combination? The “COMBO-DN study”—a naproxen in patients with cardiothrombotic diseases and ar- multinational, randomized, double-blind, parallel-group study thritis after upper gastrointestinal bleeding (CONCERN): an in- in patients with diabetic peripheral neuropathic pain. Pain dustry-independent, double-blind, double-dummy, randomised 2013; 154:2616. trial. Lancet 2017; 389:2375. 46. I Gilron et al. Morphine, gabapentin, or their combination for 19. Primary prevention of ulcers in patients taking aspirin or neuropathic pain. N Engl J Med 2005; 352:1324. NSAIDs. Med Lett Drugs Ther 2010; 52:17. 47. T Gomes et al. Gabapentin, opioids, and the risk of opioid- 20. Naproxen/esomeprazole (Vimovo). Med Lett Drugs Ther 2010; related death: a population-based nested case-control study. 52:74. PLoS Med 2017; 14:e1002396. 21. A fi xed-dose combination of ibuprofen and famotidine (Duexis). 48. M Sanford. Intrathecal ziconotide: a review of its use in pa- Med Lett Drugs Ther 2011; 53:85. tients with chronic pain refractory to other systemic or intra- 22. S Trelle et al. Cardiovascular safety of non-steroidal anti- thecal analgesics. CNS Drugs 2013; 27:989. inflammatory drugs: network meta-analysis. BMJ 2011; 49. GC McDowell 2nd and JE Pope. Intrathecal ziconotide: dos- 342:c7086. ing and administration strategies in patients with refractory 23. P McGettigan and D Henry. Cardiovascular risk with non-ste- chronic pain. Neuromodulation 2016; 19:522. roidal anti-inflammatory drugs: systematic review of popula- 50. Ziconotide (Prialt) for chronic pain. Med Lett Drugs Ther 2005; tion-based controlled observational studies. PLoS Med 2011; 47:103. 8:e1001098. 51. CJ Derry et al. as an analgesic adjuvant for acute pain 24. KB Sondergaard et al. Non-steroidal anti-inflammatory drug in adults. Cochrane Database Syst Rev 2014; 12:CD009281. use is associated with increased risk of out-of-hospital cardiac 52. J Park and HJ Park. Botulinum toxin for the treatment of neu- arrest: a nationwide case-time-control study. Eur Heart J Car- ropathic pain. Toxins (Basel) 2017; 9:E260. diovasc Pharmacother 2017; 3:100. 53. PF Whiting et al. Cannabinoids for medical use: a systematic 25. SE Nissen et al. Cardiovascular safety of celecoxib, naproxen, or review and meta-analysis. JAMA 2015; 313:2456. ibuprofen for arthritis. N Engl J Med 2016; 375:2519. 54. Cannabis and cannabinoids. Med Lett Drugs Ther 2016; 26. Celecoxib safety revisited. Med Lett Drugs Ther 2016; 58:159. 58:97. 27. TK Choueiri et al. Analgesic use and the risk of kidney cancer: 55. SM Nugent et al. The effects of cannabis among adults with a meta-analysis of epidemiologic studies. Int J Cancer 2014; chronic pain and an overview of general harms: a systematic 134:384. review. Ann Intern Med 2017; 167:319. 28. AK Chang et al. Effect of a single dose of oral opioid and nono- 56. PS Davies and BS Galer. Review of lidocaine patch 5% stud- pioid analgesics on acute extremity pain in the emergency de- ies in the treatment of postherpetic neuralgia. Drugs 2004; partment: a randomized . JAMA 2017; 318:1661. 64:937. 29. W Häuser et al. The role of antidepressants in the management 57. Capsaicin patch (Qutenza) for postherpetic neuralgia. Med of fi bromyalgia syndrome: a systematic review and meta-anal- Lett Drugs Ther 2011; 53:42. ysis. CNS Drugs 2012; 26:297. 58. FDA. Drug Safety Communication: rare cases of serious burns 30. R Aiyer et al. Treatment of neuropathic pain with venlafaxine: a with the use of over-the-counter topical muscle and joint systematic review. Pain Med 2017; 18:1999. pain relievers. Available at www.fda.gov/Drugs/DrugSafety/ 31. LA VanderWeide et al. A systematic review of the effi cacy of ucm318858.htm. Accessed February 1, 2018. venlafaxine for the treatment of fi bromyalgia. J Clin Pharm Ther 59. J Schneiderhan et al. Primary care of patients with chronic 2015; 40:1. pain. JAMA 2017; 317:2367. 32. Duloxetine (Cymbalta) for diabetic neuropathic pain. Med Lett 60. RB Saper et al. Yoga, physical therapy, or education for chron- Drugs Ther 2005; 47:67. ic low back pain: a randomized noninferiority trial. Ann Intern 33. Duloxetine (Cymbalta) for fi bromyalgia. Med Lett Drugs Ther Med 2017; 167:85. 2008; 50:57. 61. LJ Geneen et al. Physical activity and exercise for chronic pain 34. Duloxetine (Cymbalta) for chronic musculoskeletal pain. Med in adults: an overview of Cochrane Reviews. Cochrane Data- Lett Drugs Ther 2011; 53:33. base Syst Rev 2017; 4:CD011279. 35. Milnacipran (Savella) for fi bromyalgia. Med Lett Drugs Ther 2009; 51:45. 36. NB Finnerup et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol Follow us on Twitter Like us on Facebook 2015; 14:162.

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Nonopioid Drugs for Pain 6. Which of the following NSAIDs does not interfere with platelet function and prolong bleeding time? 1. Unlike full opioid agonists, acetaminophen and NSAIDs: a. ibuprofen a. have anticholinergic effects b. naproxen b. cannot be used in patients with renal impairment c. celecoxib c. have a dose ceiling on their analgesic effect d. diclofenac d. are not metabolized in the liver 7. Which of the following decreases renal blood flow and may 2. Unlike NSAIDs, acetaminophen: cause hypertension and renal failure, particularly in elderly a. has clinically signifi cant anti-inflammatory activity patients? b. can cause fatal hepatotoxicity in overdose a. acetaminophen c. is not safe for use in pregnancy b. opioids d. has no clinically signifi cant drug interactions c. celecoxib 3. Which of the following irreversibly inhibits platelet function for d. all of the above the 8- to 10-day life of the platelet? 8. A 34-year-old woman in the second trimester of pregnancy has a. aspirin been taking ibuprofen as adjunctive treatment for rheumatoid b. acetaminophen arthritis pain. She asks you if that could harm the baby. You c. ibuprofen could tell her that: d. naproxen a. there is no evidence that ibuprofen causes fetal harm 4. A 44-year-old former baseball pitcher is experiencing b. use of ibuprofen during pregnancy decreases the risk of intermittent pain in his pitching shoulder despite exercise and miscarriage massage therapy. An MRI has revealed no structural damage c. use of ibuprofen in the third trimester of pregnancy may that could be repaired surgically. Which of the following should cause premature closure of the ductus arteriosus in the you recommend for treatment of pain in this patient? neonate a. an opioid d. it is safe to continue taking ibuprofen until delivery b. an NSAID 9. The mainstays of treatment for neuropathic pain syndromes are: c. gabapentin a. antidepressants and antipsychotics d. ziconotide b. antidepressants and antiepileptics 5. Which of the following is most effective for treatment of acute c. opioids pain? d. COX-2-selective NSAIDs a. aspirin 10. For treatment of severe chronic pain, ziconotide is b. acetaminophen administered: c. celecoxib a. orally d. naproxen b. subcutaneously c. intramuscularly d. intrathecally

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