Drugs for pain

Most healthy patients can take up to 4 repeated use of such doses was associated with Continued use of acetaminophen may increase the anti-coagulant effect of warfarin Coumadin, and gene

Treatment Guidelines

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Drugs for Pain

Tables

Treatment Guidelines

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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 respon-sive 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

NONOPIOID ANALGESICS

The maximum analgesic effect of acetaminophen and aspirin usually occurs with single doses between 650 and 1300 mg With nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin, the analgesic ceil-ing may be higher Tolerance does not develop to the analgesic effects of these drugs

ACETAMINOPHEN — Acetaminophen has no

clin-ically significant anti-inflammatory activity and is less effective than full doses of NSAIDs, but has fewer adverse effects It is available in multiple oral formu-lations, often in combination with other OTC and pre-scription drugs It is also available in rectal and

Acetaminophen overdose can cause serious or fatal hepatotoxicity, and in some patients, such as those who are fasting, are heavy alcohol users, or are con-currently taking isoniazid (INH), zidovudine

(Retrovir, and others) or a barbiturate, it can develop

after moderate overdosage or even with high thera-peutic doses Most healthy patients can take up to 4

repeated use of such doses was associated with

Continued use of acetaminophen may increase the

anti-coagulant effect of warfarin (Coumadin, and generics) in

some patients.4Acetaminophen at a dose of 1 gram three

RECOMMENDATIONS

Nociceptive pain can be treated with nonopioid

analgesics or opioids Neuropathic pain is less

responsive to opioids and is often treated with

adju-vant drugs such as antidepressants and

antiepilep-tics Combining different types of analgesics may

provide an additive analgesic effect without

increas-ing adverse effects

Mild to Moderate Pain – Nonopioid analgesics

such as aspirin, acetaminophen and nonsteroidal

anti-inflammatory drugs (NSAIDs) are preferred for

initial treatment of mild to moderate pain For

mod-erate acute pain, most NSAIDs are more effective

than aspirin or acetaminophen and some have shown

equal or greater analgesic effect than an oral opioid

combined with acetaminophen, or even injected

opi-oids The selective COX-2 inhibitor celecoxib

appears to cause less severe GI toxicity than

non-selective NSAIDs Moderate pain that does not

respond to nonopioids can be treated with a

combi-nation of opioid and nonopioid analgesics

Severe Pain – For treatment of most types of severe

pain, full opioid agonists are the drugs of choice

Unlike NSAIDs, morphine and the other full agonists

generally have no dose ceiling for their analgesic

effectiveness except that imposed by adverse effects

Patients who do not respond to one opioid may

respond to another Meperidine use should be

discour-aged because of the high rate of CNS toxicity and the

availability of less toxic, longer-acting alternatives

Tolerance to most of the adverse effects of opioids,

including respiratory and CNS depression, develops at

least as rapidly as tolerance to the analgesic effect;

tol-erance can usually be surmounted and adequate

anal-gesia restored by increasing the dose When frequent

dosing becomes impractical, long-acting opioids may

be helpful

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Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013 33

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

32

Acetaminophen is included in multiple prescription and OTC products for treatment of pain, cough, cold, flu, migraine, $1.31 insomnia, etc., increasing the risk for accidental overdosage; the FDA is asking drug manufacturers to limit the 3.92 amount of acetaminophen in prescription products to 325 mg.

348.04 3

Available in chewable, buffered, enteric-coated and extended-release formulations 1.12

4

500 mg comparable to 650 mg of aspirin or acetaminophen with slower onset and longer duration 17.78

15.68 Comparable to aspirin with longer duration; available in enteric-coated and extended-release tabs ( Voltaren, 7.56

others); available with misoprostol (Arthrotec) to decrease GI toxicity; also approved as topical patch (Flector) 102.06 for treatment of pain due to minor strains, sprains and contusions, a gel (Voltaren 1% Gel) for topical 79.80 relief of osteoarthritis pain, and a topical solution (Pennsaid 1.5%) for treatment of osteoarthritis of the knee.

200 mg comparable to ibuprofen 400 mg; possibly superior to 650 mg of aspirin; also available as 13.65 extended-release tabs with a maximum daily dose of 1200 mg.

Also available in generic 600 mg tabs for treatment of rheumatoid arthritis or osteoarthritis 21.56 FDA-approved only for use in osteoarthritis and rheumatoid arthritis 3.22

29.38

200 mg equal to 650 mg of aspirin or acetaminophen, 400 mg superior with longer duration; 400 mg 2.24 comparable to acetaminophen/codeine combination; also available in combination with famotidine (Duexis).

Has a modest opioid-sparing effect; effectiveness compared to ketorolac unclear 205.80

0.56 2.43

25 mg comparable to ibuprofen 400 mg and superior to 650 mg of aspirin; 50 mg superior to acetaminophen/ 2.94 codeine combination; maximum daily dose of extended-release capsule is 200 mg.

Recommended only for continuation therapy after IM or IV ketorolac; total use of ketorolac not to exceed 5 days; 9.60 5

10 mg comparable to aspirin or acetaminophen; 20 mg comparable to ibuprofen 400 mg.

Comparable to 12 mg IM morphine with longer duration; use should be limited to 5 days because 10.70 5

of GI toxicity; can also be given as a single IM dose of 60 mg (<65 yrs) or 30 mg (>65 yrs).

Dose in patients weighing <50 kg or with renal impairment (GFR 30-90 mL/min) is 1 spray in one nostril; 165.00 6

maximum 4 doses/day for up to 5 days.

91.77 Comparable to aspirin, but more effective in dysmenorrhea; duration of use not to exceed 1 week 376.88

or 2-3 days for dysmenorrhea 571.48 FDA-approved only for use in osteoarthritis and rheumatoid arthritis; appears to be more selective for COX-2 0.49 than COX-1 at low doses (7.5 mg) 36.67 FDA-approved only for use in osteoarthritis and rheumatoid arthritis 6.72

250 mg probably comparable to 650 mg of aspirin with longer duration; 500 mg superior to 650 mg of aspirin; 1.47 also available in a fixed-dose combination (Vimovo) with the proton pump inhibitor esomeprazole 33.41

275 mg comparable to 650 mg of aspirin with longer duration; 550 mg superior to 650 mg of aspirin with longer 3.57

440 mg comparable to 400 mg of ibuprofen with longer duration 1.82 Less effective than full doses of naproxen or ibuprofen 73.26

4 Cost of 100 tabs at www.cvs.com Accessed March 11, 2013.

5 Cost of 5 days’ treatment for a <65 year-old patient.

6 Cost of one box containing 5 single-day bottles.

Some Available Usual Adult Maximum

Acetaminophen – generic See footnote 2 650 mg q6h or 1000 mg q8h 4000 mg

Tylenol

Ofirmev 10 mg/mL IV soln <50 kg: 15 mg/kg q6h or 12.5 mg/kg q4h 75 mg/kg

50 kg: 1000 mg q6h or 500 mg q4h 4000 mg

Salicylates

Aspirin – generic See footnote 2 325-650 mg q4-6h 4000 mg

Bayer

Diflunisal – generic 500 mg tabs 500 mg q8-12h 1500 mg

Salsalate – generic 500, 750 mg tabs 500 mg q6h or 1000 mg q12h 3000 mg

Some Non-Selective NSAIDs

Diclofenac potassium – generic 50 mg tabs 50 mg q8-12h 200 mg

Etodolac – generic 200, 300 mg caps; 200-400 mg q6-8h 1000 mg

400, 500 mg tabs;

400, 500, 600 mg ER tabs Fenoprofen – Nalfon 200, 400 mg caps 200 mg q4-6h 3200 mg

Flurbiprofen – generic 50, 100 mg tabs 100 mg q12h 300 mg

Ibuprofen – generic 400, 600, 800 mg tabs 400 mg q4-6h 2400 mg

Ibuprofen OTC – generic 100, 200 mg tabs; 200 mg caps 200-400 mg q4-6h 1200 mg

Advil, others

Ketoprofen 50, 75 mg caps; 200 mg ER caps 50 mg q6h or 75 mg q8h 300 mg

Ketorolac – generic 10 mg tabs PO: 10 mg q4-6h 40 mg

15 mg/mL, 30 mg/mL, IM or IV: <65 yrs: 30 mg q6h 120 mg

60 mg/2 mL injection >65 yrs: 15 mg q6h 60 mg

Sprix 15.75 mg/intranasal spray <65 yrs: 1 spray q6-8h in each nostril 126 mg

>65 yrs: 1 spray q6-8h in one nostril 63 mg Meclofenamate – generic 50, 100 mg caps 50-100 mg q4h 400 mg

Mefenamic acid – generic 250 mg caps 250 mg q6h 1250 mg first day

Meloxicam – generic 7.5, 15 mg tabs; 7.5 mg/5mL 7.5-15 mg q24h 15 mg

Nabumetone – generic 500, 750 mg tabs 500-750 mg q8-12h 2000 mg

Naproxen – generic 250, 375, 500 mg tabs; 250 mg q6-8h 1250 mg first day

Naprosyn, EC-Naprosyn 375, 500 enteric-coated tabs; or 500 mg q12h then 1000 mg

25 mg/mL PO susp Naproxen sodium – generic 275, 550 mg tabs 275 mg q6-8h 1375 mg first day

Naproxen sodium OTC – generic 220 mg tabs 220 mg q8-12h 660 mg

Aleve

Selective COX-2 Inhibitor

Celecoxib – Celebrex 50, 100, 200, 400 mg caps 200 mg q12h 600 mg first day

then 400 mg

1 Wholesale acquisition cost of 1 weeks’ treatment with the lowest dose and/or longest dosing interval $ource® Monthly (Selected from FDB MedKnowledge™)

March 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

2 Available in multiple strengths and dosage forms, alone and in combination with other drugs, both OTC and by prescription.

3 Cost based on treatment of a 70-kg patient.

Table 1 Some Nonopioid Analgesics

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

times daily for 2 weeks has been shown to increase blood

pressure slightly in patients with cardiovascular disease.5

Occasional use of oral acetaminophen during

pregnan-cy is generally considered safe IV acetaminophen

(Ofirmev) is classified as category C (risk cannot be

ruled out) for use during pregnancy

SALICYLATES — Aspirin is effective for most types

of mild to moderate pain, but now it is mainly used in

low doses as a platelet inhibitor Unlike other NSAIDs,

a single dose of aspirin irreversibly inhibits platelet

function for the 8- to 10-day life of the platelet,

inter-fering with hemostasis and prolonging bleeding time A

single dose of aspirin can precipitate asthma symptoms

in aspirin-sensitive patients High doses or chronic use

of aspirin can cause GI ulceration and salicylate

intox-ication Taking buffered or enteric-coated formulations

can reduce GI upset but does not reduce the risk of GI

ulceration, and could delay pain relief Aspirin should

not be used during viral syndromes in children and

teenagers because of the risk of Reye’s syndrome

Nonacetylated salicylates such as diflunisal or

sal-salate do not interfere with platelet aggregation, are

rarely associated with GI bleeding, and are well

toler-ated by asthmatic patients, but there are no controlled

trials demonstrating their comparative efficacy for

treatment of chronic pain

NSAIDs — The effects of NSAIDs are mainly due to

inhibition of the two isoforms of cyclooxygenase,

COX-1 and COX-2 COX-1 is expressed in most

tis-sues and is thought to protect the gastric mucosa

COX-2 is expressed in various tissues, especially in the

kid-ney, where it helps to maintain perfusion Inhibition of

COX-1 decreases synthesis of thromboxane in platelets

interfering with platelet aggregation Inhibition of

COX-2 is responsible for the anti-inflammatory effect

of NSAIDs At therapeutic doses, the older traditional

NSAIDs such as ibuprofen or naproxen block both

iso-forms to varying degrees, while COX-2-selective

inhibitors such as celecoxib selectively inhibit COX-2

In single full doses, most non-selective NSAIDs are

more effective than full doses of acetaminophen or

aspirin for treatment of acute pain, and some have

shown equal or greater analgesic effect than usual

doses of an oral opioid combined with acetaminophen,

or even injected opioids Celecoxib is about as

effec-tive as non-seleceffec-tive NSAIDs for treatment of

osteoarthritis and rheumatoid arthritis.6It seems to be

less effective for treatment of acute pain, such as that

following surgical or dental procedures Intramuscular

or intravenous ketorolac is comparable in analgesic

efficacy to moderate doses of morphine How NSAIDs

compare to other analgesics for treatment of chronic

34

pain is less well established Some patients may respond better to one NSAID than another

Diclofenac is available for topical use as a patch

(Flector), a topical gel (Voltaren 1% Gel) and a topical

solution (Pennsaid 1.5% Solution) for local treatment

of osteoarthritis or musculoskeletal pain Applying the drug topically appears to be modestly effective in reducing pain with a low risk of systemic side effects

Bleeding – All NSAIDs, except celecoxib and, to a

lesser extent, meloxicam and nabumetone, can interfere with platelet function and prolong bleeding time Unlike aspirin, which has an irreversible inhibitory effect on platelets that persists for the life of the platelet (8-10 days), the NSAID-induced antiplatelet effect is reversible when the NSAID is cleared

GI Adverse Effects – Dyspepsia and GI ulceration,

perforation and bleeding can occur with all NSAIDs, including parenteral formulations, often without warn-ing High doses, prolonged use, previous peptic ulcer disease, concomitant systemic corticosteroid or aspirin therapy (even 81 mg/day), excessive alcohol intake and advanced age increase the risk of these complications Celecoxib appears to cause less GI toxicity than non-selective NSAIDs Diclofenac, etodolac, meloxicam

and nabumetone are somewhat COX-2 selective in

vitro Theoretically, these drugs may cause less GI

toxicity than less selective NSAIDs such as ibuprofen, but there are no clinical data showing that they are less likely to cause serious GI complications, and only weak data suggesting that they are less likely to cause symptomatic ulcers

Concurrent use of a proton pump inhibitor such as

omeprazole (Prilosec, and generics), an H2-receptor antagonist such as ranitidine (Zantac, and generics), or the prostaglandin analog misoprostol (Cytotec, and

generics) may decrease the incidence of GI toxicity

(diclofenac/misopros-tol), Vimovo (naproxen/esomeprazole) and Duexis

(ibuprofen/famotidine) are three commercially-available combinations of an NSAID and an agent for

GI protection.8,9

Renal Toxicity – All NSAIDs, including celecoxib,

inhibit renal prostaglandins, decrease renal blood flow, cause fluid retention, and may cause hypertension and renal failure in some patients, particularly the elderly Diminished renal function or decreased effective intravascular volume due to diuretic therapy, cirrhosis

or heart failure increases the risk of NSAID-induced renal toxicity

Cardiovascular Effects – An increased risk of serious

cardiovascular events such as myocardial infarction or

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

stroke has been reported with some NSAIDs; the risk

appeared to be highest with diclofenac and lowest with

with higher doses of the drug, but it appears to be

simi-lar to that of non-selective NSAIDs.13 Other analgesics

should generally be tried first in patients with

cardio-vascular disease.14

Other Effects – Like aspirin, NSAIDs can precipitate

asthma and anaphylactoid reactions in

aspirin-sensi-tive patients NSAIDs frequently cause small

increas-es in aminotransferase activity; serious hepatotoxicity

is rare, but may occur more frequently with diclofenac

Pancreatitis has been reported Cholestatic hepatitis

has occurred with celecoxib, possibly related to

sul-fonamide allergy; celecoxib is contraindicated in

patients allergic to sulfonamides

NSAIDs can cause central nervous system effects such

as dizziness, anxiety, drowsiness, confusion,

depres-sion, disorientation, severe headache and aseptic

menin-gitis They have been associated with both mild and

severe skin reactions, including exfoliative dermatitis,

Stevens-Johnson syndrome and toxic epidermal

necrol-ysis NSAIDs rarely cause blood dyscrasias; aplastic

anemia has been reported with ibuprofen, fenoprofen,

naproxen, indomethacin, tolmetin and piroxicam

Long-term use of nonaspirin NSAIDs was associated with an

increased risk of renal cell cancer in one report.15

Pregnancy – Exposure to NSAIDs during pregnancy

or around the time of conception has been associated

with an increased risk of miscarriage, but the data are

weak Use of NSAIDs during the third trimester of

pregnancy may cause premature closure of the

duc-tus arteriosus and persistent pulmonary hypertension

in the neonate, but these effects appear to be

uncom-mon if the drug is discontinued 6-8 weeks before

delivery

Drug Interactions – NSAIDs may decrease the

effec-tiveness of diuretics, beta-blockers, ACE inhibitors

and some other antihypertensive drugs, and may

increase the toxicity of lithium and methotrexate They

may increase INR if taken with warfarin Patients

tak-ing aspirin for cardiovascular protection should not

take ibuprofen regularly because it can interfere with

aspirin’s antiplatelet effect

OPIOIDS

Opioids can be categorized as full agonists, partial

ago-nists or mixed agonist/antagoago-nists Full agoago-nists are

generally used for treatment of moderate to severe

acute or chronic pain Unlike NSAIDs, most opioids

have no ceiling for their analgesic effectiveness, except

that imposed by adverse effects

FULL AGONISTS — Morphine – Given orally,

mor-phine is well absorbed but undergoes extensive first-pass metabolism, resulting in a low bioavailability of about 35% Morphine should be used with caution in patients with severe renal insufficiency because accu-mulation of an active neurotoxic metabolite may cause agitation, confusion, delirium and other adverse effects

Oxycodone – Oxycodone, a semi-synthetic derivative

of the opioid alkaloid thebaine, is only available orally

It is about 9.5 times more potent than oral codeine and

is frequently used in combination with acetaminophen for treatment of acute pain The long-acting formulation

is commonly used for treatment of chronic pain due to cancer New tamper-deterrent formulations have reduced abuse of oxycodone, but abuse of other opioids has increased.17,18

Oxymorphone – A metabolite of oxycodone,

oxymor-phone is available in parenteral and short- and

than oral morphine Long-acting oxymorphone can provide adequate pain relief in cancer patients

Hydromorphone – A semi-synthetic opioid,

hydro-morphone is available in parenteral, rectal and

study in patients with chronic noncancer pain, once-daily hydromorphone was similar in efficacy to

Hydromorphone may be a safer choice than morphine

in patients with renal insufficiency

Fentanyl – Fentanyl is available in IV, intrathecal,

epidural, transdermal, intranasal and oral transmucosal formulations Transdermal fentanyl offers a convenient delivery system for patients with chronic pain, partic-ularly those with difficulty swallowing or malabsorp-tion, but should be started only after initial titration with a short-acting opioid Patients should be warned that exposing a fentanyl patch to heat, from either an external source (e.g., a heating pad), increased exer-tion, or high fever, could increase release of the drug

use of drugs that inhibit CYP3A4, especially strong

inhibitors such as ketoconazole (Nizoral, and generics)

or clarithromycin (Biaxin, and generics), can cause

dangerous increases in fentanyl serum

accidental exposure to the patch.25

Several oral transmucosal formulations (lozenge, buccal tablet and film, sublingual tablet and nasal and sublingual sprays) are available for management of breakthrough pain in cancer patients

35

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013 37

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

36

Table 2 Some Opioid Analgesics

Oral/Topical Adult Starting Duration Substance Pregnancy

Full Agonists

Codeine – generic 15, 30, 60 mg tabs; 30 mg/5 mL PO soln 15-60 mg q4h 4 hrs II-V 3 C 60 mg PO equivalent to 650 mg of aspirin or acetaminophen; 10% of people lack the $0.34

enzyme needed to make codeine active and others rapidly metabolize codeine to morphine increasing the risk of respiratory depression; also available in fixed-dose combinations with acetaminophen ( Tylenol/Codeine No 3, others) for treatment of pain.

Fentanyl 4 II C Not recommended for opioid-nạve patients; standard dose determined by

Transdermal – previous opioid dosage.

Transmucosal – Abstral, Actiq, Fentora, Lazanda, Onsolis and Subsys are indicated

Abstral (ProStrakan) 100, 200, 300, 400, 600, 800 mcg 100 mcg >1 hr only for breakthrough pain Actiq may cause dental caries 14.00

sublingual tabs

Hydrocodone See comments 5-10 mg q4-6h 4 hrs III C Currently only available for treatment of pain in fixed-dose combinations with 0.23 8

acetaminophen ( Vicodin, others) or ibuprofen (Vicoprofen, others), but awaiting FDA

approval as an individual agent; 10 mg equivalent to codeine PO 60-80 mg.

Hydromorphone 4 II C Also available as a high potency injectable (Dilaudid-HP, generics) and as

Levorphanol – generic 2 mg tabs 2 mg q6-8h 6-8 hrs II C Accumulation may occur with chronic use 1.56

Meperidine 4 II C More rapid onset of action than morphine; toxic metabolite with long half-life

Demerol (Sanofi) 50, 75, 100, 150 mg tabs; 50 mg/5 mL PO soln 50 mg q3-4h 9 3-4 hrs causes CNS excitation and convulsions; tissue irritation occurs with 1.84

generic parenteral use; use should be limited to 48 hours 0.28

Methadone 4 – generic 5, 10, mg tabs; 5, 10 mg/5 mL PO soln, 2.5-10 mg q8-12h 8-12 hrs II C Accumulation may occur with chronic use 0.13

10 mg/mL PO conc

Morphine 4 – generic 15, 30 mg tabs; 20 mg/mL, 10, 20, 100 mg/5 mL 10-30 mg q4h II C Also available for intrathecal and epidural use and as a suppository 0.20

PO soln

Kadian (Actavis) 10, 20, 30, 40, 50, 60, 70, 80, 100, 130, 150, See footnote 5 12 hrs Taking Kadian or Avinza with alcohol can result in rapid release of morphine, 4.88 10

200 mg ER caps which could be fatal; maximum dose of Avinza is 1600 mg due to renal toxicity of

generic 20, 30, 50, 60, 80, 100 mg ER caps fumaric acid in the beads; chewing or crushing the beads can be fatal 4.18

Morphine/naltrexone – Embeda 20/0.8, 30/1.2, 50/2, 60/2.4, 80/3.2, 100/4 mg caps See footnote 5 12-24 hrs II C Naltrexone is only absorbed if the capsules are crushed, chewed or dissolved; taking 4.15

(Pfizer) Embeda with alcohol can result in increased plasma levels of morphine; currently

unavailable due to voluntary recall.

Oxycodone – generic 5 mg caps; 5, 10, 15, 20, 30 mg tabs; 5-15 mg q4-6h 4-6 hrs II B Also available in a fixed-dose combination with acetaminophen ( Percocet, others), 0.18

5 mg/5 mL, 20 mg/mL PO soln aspirin ( Percodan, others) or ibuprofen (Combunox); Oxecta and OxyContin have

Oxymorphone 4 II C No CYP drug interactions.

Opana ER 5, 7.5, 10, 15, 20, 30, 40 mg ER tabs 10 mg q12h 5 12 hrs Taking long-acting oral oxymorphone with alcohol can result in substantial increases 1.89

generic in peak serum concentrations of the drug, which could be fatal 1.45

Agonist/Reuptake Inhibitors

Tapentadol II C Mu-receptor agonist and norepinephrine reuptake inhibitor; fewer 2.23

Nucynta (Janssen) 50, 75, 100 mg tabs 50-100 mg q4-6h 4-6 hrs GI adverse effects, but similar CNS effects compared to some other opioid 2.55

Tramadol None 11 C Weak agonist/norepinephrine and serotonin reuptake inhibitor; variable

generic by starting with 25 mg/day and slowly titrating to usual dose over a few weeks; 0.11

Rybix (Shionogi) 50 mg orally disintegrating tabs 50 mg q4-6h 4-6 hrs 50 mg equivalent to codeine 60 mg; 100 mg comparable to aspirin 650 mg plus 2.72

Ultram ER (Janssen) 100, 200, 300 mg ER tabs 100 mg once/d 5 24 hrs codeine 60 mg; maximum dose 400 mg/d for IR and 300 mg/d for ER; also avail- 4.92

generic able in a fixed-dose combination with acetaminophen ( Ultracet, others) 2.77

multiphase generic 100, 200, 300 mg ER tabs 13 ; 150 mg ER caps 100 mg once/d 5 24 hrs 3.47

1 FDA Pregnancy Categories: B = no evidence of risk in humans; C = risk cannot be ruled out 8 Cost of one dose of hydrocodone 5 mg/acetaminophen 325 mg.

2 Wholesale acquisition cost (WAC) of a single dose at the lowest available strength $ource® Monthly (Selected from FDB MedKnowledge™) March 5, 2013 9 Oral meperidine is not recommended for treatment of acute or chronic pain.

Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher 10 Cost of 20 mg ER cap.

3 Single-agent codeine is schedule II; fixed dose combinations containing acetaminophen are schedule III or V 11 Tramadol is not a federally controlled substance in the US, but many states and the US military have it classified as a schedule IV controlled sub-

4 Also available parenterally stance under state law.

5 Starting dose determined by previous opioid dosage Long-acting formulations are generally not recommended for opioid-naive patients 12 Mixture of immediate-release (IR) and extended-release (ER) tramadol: 100 mg contains 25 mg IR and 75 mg ER, 200 mg contains 50 mg IR and

6 Some patients need to change the patch every 48 hours to achieve adequate analgesia 150 mg ER, 300 mg contains 50 mg IR and 250 mg ER.

7 Cost of one bottle containing 8 sprays 13 Generic equivalent of Ryzolt (Purdue), which has been discontinued.

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

Methadone – Methadone is used parenterally and

orally for treatment of chronic pain.26-28In one study

of first-line treatment of cancer pain, methadone was

similar to long-acting morphine.29The plasma half-life

of methadone is variable and can be as long as 5 days;

repeated doses can lead to accumulation and CNS

depression without close monitoring during the

titra-tion period Methadone is not fully cross-tolerant with

other opioid agonists Switching from another opioid

agonist to methadone should be done cautiously; the

equianalgesic dose of methadone is not well

estab-lished in opioid-tolerant patients Methadone has no

active metabolites, which may be advantageous in

patients with renal insufficiency Dose-related QT

interval prolongation, torsades de pointes and death

Levorphanol – Oral levorphanol is used to treat

chronic pain It has a long half-life (16-18 hours) and

can accumulate with repeated dosing Like methadone,

levorphanol also exhibits incomplete cross-tolerance

when converting from other opioids and requires

care-ful dose titration

Meperidine – Meperidine should only be used for

short-term (24-48 hours) treatment of moderate to

severe acute pain It has a more rapid onset of action

than morphine, but is shorter acting It is highly

irritat-ing to tissues when given subcutaneously, and when

given IM, can cause muscle fibrosis Repeated doses of

the drug can lead to accumulation of normeperidine, a

toxic metabolite with a 15- to 30-hour half-life

Normeperidine can cause dysphoria, irritability,

tremors, myoclonus and, occasionally, seizures,

partic-ularly with patient-controlled analgesia or in elderly

patients or those with impaired renal function In

patients who are taking or have recently stopped taking

a monoamine oxidase inhibitor, meperidine can cause

severe encephalopathy and death

Codeine – Codeine is an oral opioid agonist with a

long history of use as an analgesic and cough

suppres-sant Codeine is converted to morphine, its active

form, by the hepatic enzyme CYP2D6 Some patients

are considered CYP2D6 “ultra-metabolizers” and

rapidly convert codeine to higher than usual levels of

morphine, resulting in toxicity There is emerging

evi-dence that significant side effects, including death, can

occur even at usual doses, particularly in children with

genetic variations in drug metabolism Codeine is now

contraindicated for use in children undergoing

CYP2D6 poor metabolizers (up to 10% of the

popula-tion) or are taking drugs that inhibit CYP2D6, such as

fluoxetine (Prozac, and generics), cannot convert

codeine to morphine and may not experience any

anal-gesic effect

38

Hydrocodone – Hydrocodone is a synthetic opioid that

is metabolized to hydromorphone after oral administra-tion For treatment of pain, this widely prescribed opi-oid is available only in combination with acetamino-phen or ibuprofen; it is currently under review by the FDA for approval as a single agent The efficacy of the combination of hydrocodone and acetaminophen is similar to that of codeine plus acetaminophen

FULL AGONIST/REUPTAKE INHIBITORS — Tapentadol – Tapentadol is an oral opioid receptor

extended-release formulation of the drug appears to provide analgesic efficacy similar to that of extended-release oxycodone for osteoarthritis and low back pain

appear to have significant serotonergic activity, the drug’s labeling carries a warning about the possibility

of serotonin syndrome when used concurrently with serotonergic drugs Due to its adrenergic effects, it should not be used with or within 14 days of taking a monoamine oxidase inhibitor

Tramadol – An oral centrally-acting opioid agonist

that blocks reuptake of norepinephrine and serotonin, tramadol is used to treat moderate to moderately severe pain Its effectiveness in combination with acetamino-phen for treatment of chronic pain is comparable to that of combinations of acetaminophen with codeine or oxycodone The need for slow-dose titration to improve tolerability when initiating tramadol limits its use for treatment of acute pain Tramadol is also effec-tive for treatment of neuropathic pain.35

Seizures have been reported with tramadol; according

to the manufacturer, patients with a history of seizures and those concomitantly taking a tricyclic antidepres-sant or selective serotonin reuptake inhibitor, an MAO inhibitor, other opioids or an antipsychotic drug may

be at increased risk As with codeine, much of tra-madol’s analgesic efficacy is due to its active metabo-lite, and inhibition of CYP2D6 may decrease its effi-cacy Concurrent use of tramadol with drugs that inhibit CYP2D6 or 3A4 can decrease tramadol clear-ance and increase seizure risk The labeling warns of

a possible increased risk of suicide in patients who are suicidal, emotionally disturbed or prone to addiction Tramadol is not federally classified as a controlled substance, but in many states it is classified as a schedule IV controlled substance, as psychological and physical dependence have occurred

OTHERS — The partial agonist buprenorphine and

the mixed agonist/antagonists pentazocine,

butor-phanol and nalbuphine all have a ceiling on their

analgesic effects and can precipitate withdrawal symptoms in patients physically dependent on full

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

agonists All are less likely than full agonists to cause

physical dependence, but none is entirely free of

dependence liability

Buprenorphine is available in a transdermal patch

(Butrans) for treatment of chronic pain In some

stud-ies, application of one patch every 7 days was effective

in reducing pain in patients with chronic back pain

Erythema and pruritus at the site of patch application,

nausea, headache, dizziness and somnolence are

com-mon adverse effects Doses >20 mcg/hr are not

the low maximum dose, the patch is not useful for

treatment of severe cancer pain Patients maintained on

buprenorphine may require higher than normal doses

of full opioid agonists during and for up to 48 hours

following discontinuation of the patch Buprenorphine

is also available parenterally (Buprenex, and generics)

for treatment of pain and as sublingual tablets alone

and in combination with naloxone (Suboxone) for

OPIOID ADVERSE EFFECTS — Sedation,

dizzi-ness, nausea, vomiting, pruritus, sweating and

consti-pation are the most common adverse effects of opioids;

respiratory depression is the most serious Usual doses

of opioids, including the mixed agonist/antagonists,

may decrease respiratory drive and cause apnea in

opi-oid-naive acute-pain patients, particularly those who

have chronic obstructive pulmonary disease, cor

pul-monale, decreased respiratory reserve or pre-existing

respiratory depression The addition of general

anes-thetics, phenothiazines, sedative-hypnotics such as

ben-zodiazepines or barbiturates, tricyclic antidepressants,

or other CNS depressants increases the risk of

respira-tory depression Patients who take opioids chronically

are often tolerant to the respiratory depressant effect

Persistent opioid-induced sedation that limits activity

can be ameliorated by giving small oral doses of

stim-ulants such as methylphenidate (Ritalin, and generics)

in the morning and early afternoon The narcolepsy

drug modafinil (Provigil, and generics) has also been

Tolerance usually develops rapidly to the sedative and

emetic effects of opioids, but not to constipation; a

stimulant laxative with or without a stool softener

should be started early in treatment The selective

opi-oid antagonist methylnaltrexone (Relistor) is

FDA-approved for treatment of opioid-induced

constipa-tion.39,40 Transdermal fentanyl may cause less

consti-pation than sustained-release oral morphine

Opioids can increase prolactin levels and reduce levels

of sex hormones resulting in reduced sexual function,

decreased libido, infertility, mood disturbances and

bone loss.41

DOSAGE — Opioid dose requirements vary widely

from one patient to another, but 10 mg of oral mor-phine per 70 kg body weight, or its equivalent, is a rea-sonable starting dose For most opioids, there is gener-ally no maximum dose except when limited by the dose of aspirin, acetaminophen or ibuprofen in fixed-dose combination preparations The fixed-dose required to maintain optimum pain relief with tolerable side effects should be used After initial titration with a short-acting opioid and determination of the 24-hour dose requirement, around-the-clock dosing with a long-acting formulation is recommended for persistent chronic pain Rapid-onset opioids should be made available every 2-3 hours for breakthrough pain

TOLERANCE TO OPIOIDS — Tolerance can

develop with chronic use of opioids; the patient first notices a reduction in adverse effects and a shorter duration of analgesia followed by a decrease in the effectiveness of each dose Tolerance to most of the adverse effects of opioids develops at least as rapidly

as tolerance to the analgesic effect; it can usually be surmounted and adequate analgesia restored by increasing the dose Cross-tolerance exists among all full agonists, but is not complete; when switching to another opioid, starting with half of the customary equianalgesic dose is recommended Switching opi-oid-tolerant patients to methadone may improve pain relief, but should only be done by those prescribers who are familiar with use of methadone

PHYSICAL DEPENDENCE — Patients being

treat-ed with opioids will develop physical dependence and withdrawal symptoms will occur if the drug is discon-tinued suddenly or an opioid antagonist is given Clinically significant dependence develops only after several weeks of chronic treatment with an opioid

OPIOID-INDUCED HYPERALGESIA —

Opioid-induced hyperalgesia is a controversial condition in which patients treated with high doses of opioids experience worsening pain that cannot be overcome simply by increasing the dose (as is the case in toler-ance), but rather only by reducing the dose or com-pletely discontinuing the opioid, or changing to another opioid.42

ABUSE — Opioids have the potential for addiction

and abuse and are frequently diverted for non-medical use To reduce opioid abuse, misuse and diversion, the FDA has required the manufacturers of long-acting opioids to implement risk evaluation and mitigation strategies (REMs), including a medication guide for patients and training for prescribers

39

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

ADJUVANT PAIN MEDICATIONS

Antidepressants and antiepileptics are the mainstay of

treatment for a variety of neuropathic pain syndromes,

including postherpetic neuralgia, diabetic neuropathy,

fibromyalgia, complex regional pain syndrome and

phantom limb pain, even though most of them are not

approved by the FDA for these indications Combining

an antidepressant and an antiepileptic may produce a

synergistic analgesic effect in neuropathic pain

syn-dromes.43

ANTIDEPRESSANTS — Tricyclic antidepressants

such as amitriptyline, nortriptyline and imipramine

can relieve many types of neuropathic pain, including

diabetic neuropathy, postherpetic neuralgia,

polyneu-ropathy, and nerve injury or infiltration with cancer

analgesic effects of these drugs are likely due to their

inhibition of norepinephrine and serotonin reuptake;

their antagonism of cholinergic and histaminergic

sys-tems causes sedation, urinary retention and

hypoten-sion SSRIs appear to be less effective than tricyclic

antidepressants for treatment of neuropathic pain.45

40

Venlafaxine, a serotonin and norepinephrine reuptake

inhibitor (SNRI), has been reported to be effective in neuropathic pain and has also been used to treat headache, fibromyalgia, and postmastectomy pain syn-drome.46 It can cause a slight increase in diastolic blood pressure and discontinuation symptoms may be

trouble-some Duloxetine, another SNRI, is FDA-approved for

treatment of pain associated with diabetic peripheral neu-ropathy and fibromyalgia, and for chronic musculoskele-tal pain.47-49 In patients with chronic low back pain or osteoarthritis, it was modestly more effective than

place-bo Duloxetine appears to provide many of the analgesic benefits of older antidepressants with fewer adverse

effects Milnacipran, an SNRI approved by the FDA

only for use in fibromyalgia,50 appears to be moderately effective in decreasing pain and improving function It exhibits more selectivity for inhibition of norepinephrine reuptake than for that of serotonin How it compares to venlafaxine or duloxetine remains to be established

ANTIEPILEPTICS — In controlled trials, gabapentin has been effective in reducing pain in

postherpetic neuralgia (an FDA-approved use) and

Usual Daily

Antidepressants

Amitriptyline – generic 10, 25, 50, 75, 100, 150 mg tabs 25-100 mg once $1.30 Imipramine HCL – generic 10, 25, 50 mg tabs 50-100 mg once or divided 9.60

Imipramine pamoate – generic 75, 100, 125, 150 mg caps 75-100 mg once 348.00

Nortriptyline – generic 10, 25, 50, 75 mg caps; 75 mg once or divided 6.90

Venlafaxine – generic 25, 37.5, 50, 75, 100 mg tabs 75 mg once-tid 21.30 extended-release – generic 37.5, 75, 150 tabs and caps; 225 mg tabs 75-150 mg once 14.70

Milnacipran – Savella (Forest) 12.5, 25, 50, 100 mg tabs 50 mg bid 144.02

Antiepileptics

Gabapentin – generic 100, 300, 400 mg caps; 600, 800 mg tabs; 1800-3600 mg divided tid 64.80

extended-release

Pregabalin – Lyrica (Pfizer) 25, 50, 75, 100, 150, 200, 225, 150-600 mg divided bid or tid 220.76

300 mg caps; 20 mg/mL PO soln Carbamazepine – generic 200 mg tabs; 100 mg chewable tabs; 400-800 mg divided bid 3.00

extended-release – generic 200, 400 mg ER tabs 400-800 mg divided bid 46.20

Oxcarbazepine – generic 150, 300, 600 mg tabs; 600-1200 mg divided bid 54.60

extended-release

Oxtellar XR (Supernus) 150, 300, 600 mg ER tabs 600-2400 mg once 227.40

1 Some of the drugs listed here are not FDA-approved for use in treatment of pain.

2 Wholesale acquisition cost of 30 days’ treatment at the lowest usual dosage and/or longest dosing interval $ource® Monthly (Selected from FDB MedKnowledge™) March 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

Drugs for Pain

Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 128) • April 2013

neuropathic pain, taking lower doses of gabapentin

and morphine together provided better analgesia than

taking either drug alone.52 Gabapentin can cause

dizzi-ness, somnolence, edema and weight gain

Pregabalin, which is similar in structure to

gabapentin, is approved for treatment of neuropathic

pain associated with postherpetic neuralgia, diabetic

peripheral neuropathy, and fibromyalgia The dose of

pregabalin can be titrated more rapidly than that of

dizzi-ness, somnolence and peripheral edema; significant

weight gain has been reported in some patients

Because of some reports of euphoria, pregabalin is

classified as a Schedule V controlled substance

Carbamazepine is FDA-approved for treatment of pain

due to trigeminal neuralgia Oxcarbazepine, which is

related to carbamazepine, has been shown to provide

similar analgesia, and may have fewer adverse effects

OTHER DRUGS — Ziconotide (Prialt), a

synthet-ic neuronal N-type calcium channel blocker, is

administered intrathecally via a programmable

microinfusion device for treatment of severe chronic

pain The drug has been effective, both as

monother-apy and when added to standard thermonother-apy, for

treat-ment of refractory severe chronic pain, including

neuropathic pain Severe psychiatric effects

(para-noid reactions, psychosis) and CNS toxicity

(confu-sion, somnolence, unresponsiveness) can occur

Unlike opioids, ziconotide does not cause tolerance,

dependence or respiratory depression, and is not a

Caffeine in doses of 65-200 mg may enhance the

anal-gesic effect of acetaminophen, aspirin or ibuprofen

Hydroxyzine in doses of 25-50 mg given parenterally

may add to the analgesic effect of opioids in

postoper-ative and cancer pain while reducing the incidence of

nausea and vomiting Corticosteroids can produce

analgesia in some patients with inflammatory diseases

or tumor infiltration of nerves The oral and

transder-mal patch formulation of the alpha2-adrenergic agonist

clonidine may improve pain and hyperalgesia in

sym-pathetically maintained pain Botulinum toxin type A

administered intradermally appeared to be effective in

Although controversial, marijuana,

tetrahydro-cannabinol (Dronabinol), and a mixture of

delta9-tetrahydrocannabinol and cannabidiol (Sativex, not

approved in the US) have been shown to be effective

in multiple sclerosis patients with central neuropathic

pain and spasticity; data supporting their efficacy for

intractable cancer pain are limited.57,58

Topical Analgesics for Local Treatment – A 5%

lidocaine patch (Lidoderm) is FDA-approved for

treatment of postherpetic neuralgia.59It is widely used

off-label for other types of pain despite a lack of clin-ical trials supporting its efficacy Skin irritation can

occur at the site of application An 8% capsaicin

patch (Qutenza), available only by prescription, is

FDA-approved for treatment of postherpetic

mod-estly effective in reducing pain associated with pos-therpetic neuralgia for up to 3 months An increase in pain is common during, and for a few days after, application of the patch The patch is applied during

an office visit

Topical analgesics containing menthol, methylsalicy-late or capsaicin are available over the counter for the relief of mild muscle and joint pain While generally well-tolerated, there have been rare reports of severe skin burns requiring treatment or hospitalization.61

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25 FDA FDA reminds the public about the potential for life-threatening

41