The Medical Letter ®

on Drugs and Therapeutics

Volume 64 December 12, 2022

ISSUE IN THIS ISSUE

ISSUE No.
1433
1665
Opioids for Pain ....................................................................................................................p 193
CME: Accreditations, Disclosures, and Objectives ............................................................p 200a
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The Medical Letter ®

on Drugs and Therapeutics

Volume 64 December 12, 2022

Take CME Exams

IN THIS ISSUE
ISSUE No.
Opioids for Pain ....................................................................................................................p 193
1665 CME: Accreditations, Disclosures, and Objectives ............................................................p 200a

▶ Opioids for Pain Table 1. Opioid Prescribing for Noncancer Pain1,2

▶ Nonpharmacologic therapy and nonopioid drugs are preferred.
▶ For acute pain, opioids should be taken as needed rather than
TABLES IN THIS ISSUE around the clock.
Opioid Prescribing for Noncancer Pain...................................p 194 ▶ Opioid treatment of subacute noncancer pain (duration 1-3
Some Oral/Transdermal Opioid Analgesics .............................p 196 months) and chronic noncancer pain (duration >3 months)
should be combined with nonpharmacologic therapy and
nonopioid drugs.
A new CDC guideline for prescribing opioids for pain ▶ Immediate-release formulations are recommended for initial
opioid treatment; the lowest effective dose should be used,
recently became available.1 Nonopioid drugs for pain and the quantity prescribed should not exceed the expected
were reviewed in a previous issue.2 amount needed.
▶ Extended-release or long-acting opioids should be reserved
ACUTE PAIN — For many types of moderate to severe for patients with severe, continuous pain.
acute pain, acetaminophen and/or an NSAID may be ▶ Benefits and risks should be evaluated within 1-4 weeks of
as effective as an opioid.3,4 Use of caffeine as a co- starting treatment or of dose escalation, and at least every
3 months with continued treatment. If benefits no longer
analgesic may provide some additional pain relief.5 outweigh risks, other treatments should be optimized and
If nonopioid drugs and nonpharmacologic treatment opioids should be tapered to a lower dosage or tapered and
(e.g., heat or ice, rest, elevation, immobilization, discontinued.

physical therapy) provide insufficient relief, an ▶ Higher opioid doses are associated with increased risks for
motor vehicle injury, opioid use disorder, and overdose. Many
immediate-release formulation of a full opioid patients do not experience benefit from increasing the dose to
agonist may be used as needed (i.e., not around >50 oral morphine milligram equivalents (MMEs)/day.
the clock) at the lowest effective dose and for the ▶ Caution is recommended when opioids are prescribed
shortest possible duration. Use of extended-release concurrently with other CNS depressants, especially
benzodiazepines.
or long-acting opioid formulations initially and for
▶ The opioid antagonist naloxone should be offered to patients
treatment durations >1 week have been associated at risk of opioid overdose.
with overdose and unintended long-term use.6-8 ▶ Buprenorphine or methadone should be prescribed for patients
who develop opioid use disorder.
CHRONIC PAIN — Use of opioids for treatment of ▶ State prescription drug monitoring program data can be
chronic noncancer pain is controversial; evidence used to determine whether a patient is receiving opioid
dosages or combination treatments that increase the risk
of their long-term effectiveness from controlled for overdose.
trials is limited and serious adverse effects can ▶ Urine drug testing is recommended before starting treatment
occur.9-11 As with acute pain, nonopioid drugs and and at least annually thereafter to assess for use of other
nonpharmacologic therapy may be as effective as an controlled prescription drugs and/or illicit drugs.
1. D Dowell et al. MMWR Recomm Rep 2022; 71:1.
opioid for many types of chronic pain.12 Full opioid 2. L Manchikanti et al. Pain Physician 2017; 20(2S):S3.
agonists are recommended for treatment of severe
chronic cancer pain.
to start with 5-10 mg of oral morphine per dose (or its
DOSAGE — Opioid dosage requirements vary widely equivalent) or 20-30 mg per day (see MME conversion
among patients. In general, experts recommend factors in Table 2). After initial titration with an
starting with the lowest available strength of an immediate-release opioid, an extended-release or
immediate-release opioid and titrating to analgesic long-acting formulation can be used in patients with
effect; for opioid-naive patients, it would be reasonable continuous severe pain.
193
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 The Medical Letter ®
Vol. 64 (1665) December 12, 2022

ADVERSE EFFECTS — Sedation, dizziness, nausea, factors in Table 2). Switching opioid-tolerant patients
vomiting, pruritus, sweating, and constipation are the to methadone may improve pain relief, but should
most common adverse effects of opioids; respiratory be done cautiously by an experienced clinician;
depression is the most serious. Tolerance to the the equianalgesic dose of methadone is not well-
respiratory depressant effect develops with chronic established in opioid-tolerant patients.
use. Administered in usual doses, opioids, including
DEPENDENCE — Clinically significant physical
buprenorphine and mixed agonist/antagonists,
dependence can begin to develop after several days
may decrease respiratory drive and cause apnea
of continued treatment with an opioid. Withdrawal
in opioid-naive patients, particularly those who are
symptoms will occur if the drug is discontinued
taking other CNS depressants or have COPD, cor
suddenly or an opioid antagonist or partial agonist is
pulmonale, decreased respiratory reserve, or pre-
given. Opioids should be tapered gradually to reduce
existing respiratory depression.
withdrawal symptoms.
Tolerance usually develops rapidly to the sedative
DRUG INTERACTIONS — Use of opioids with alcohol,
and emetic effects of opioids, but not to constipation;
general anesthetics, phenothiazines, sedative-
a stimulant or osmotic laxative with or without a
hypnotics such as benzodiazepines or barbiturates,
stool softener should be started early in treatment.
tricyclic anti-depressants, first-generation antihista-
Three oral, peripherally-acting mu-opioid receptor
mines, muscle relaxants, gabapentinoids, or other
antagonists — methylnaltrexone (Relistor), naloxegol
CNS depressants increases the risk of respiratory
(Movantik), and naldemedine (Symproic) — are
depression and death. Concurrent use of an opioid and
available for treatment of opioid-induced constipation.
an anticholinergic drug can cause urinary retention and
They appear to be similar in efficacy and safety, but
severe constipation, possibly leading to paralytic ileus.
no direct comparisons are available.13-15 Lubiprostone
Use of opioids with serotonergic drugs has resulted
(Amitiza, and generics), an oral chloride channel
in serotonin syndrome, especially with fentanyl,
activator, may be less effective.16
meperidine, methadone, tapentadol, and tramadol.20
Opioid-induced hyperalgesia has been reported in Use of an opioid with or within 14 days of a monoamine
some patients treated with high doses of opioids. oxidase (MAO) inhibitor can cause serotonin syndrome
These patients experience worsening pain that or opioid toxicity and is not recommended.
cannot be overcome by increasing the dose, but
rather by reducing the dose, discontinuing the opioid, Buprenorphine, fentanyl, hydrocodone, meperidine,
or switching to another opioid.17 methadone, oliceridine, oxycodone, and tramadol
are metabolized at least partly by CYP3A4.
Chronic use of opioids can increase prolactin levels Concurrent use of a drug that inhibits CYP3A4 (or
and decrease levels of sex hormones, resulting in discontinuation of a CYP3A4 inducer) can increase
reduced sexual function, decreased libido, infertility, serum concentrations of these opioids and the risk of
mood disturbances, and bone loss.18 Adrenal sedation and respiratory depression. Concurrent use
insufficiency has been reported, typically after >1 of a drug that induces CYP3A4 (or discontinuation
month of opioid use.19 Sleep apnea, depression, falls, of a CYP3A4 inhibitor) could decrease their serum
and urinary outflow obstruction can also occur. concentrations and analgesic effect, possibly leading
TOLERANCE — Tolerance develops with chronic use of to withdrawal symptoms. Concomitant use of
opioids; the patient first notices a reduction in adverse methadone with CYP2B6, 2C19, 2C9, or 2D6 inhibitors
effects and a shorter duration of analgesia, followed (or discontinuation of inducers of these isozymes)
by a decrease in the effectiveness of each dose. It may increase methadone serum concentrations.
can usually be surmounted and adequate analgesia CYP2D6 inhibitors can decrease the analgesic effect
restored by increasing the dose or by switching to a of codeine and tramadol.21
different opioid. Tolerance to most of the adverse
Opioids delay gastric emptying and the absorption of
effects of opioids (except constipation) develops at
orally administered drugs, including the P2Y12 platelet
least as rapidly as tolerance to the analgesic effect.
inhibitors clopidogrel, prasugrel, and ticagrelor. Use
Cross-tolerance exists among all full opioid agonists, of morphine has been associated with an increased
but it is incomplete; when switching to another risk of recurrent ischemia, myocardial infarction, and
opioid, reducing the equianalgesic dose by at least death in patients taking clopidogrel after an acute
25-50% is recommended (see MME conversion coronary syndrome.22,23
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Cimetidine can potentiate the effects of morphine. for any indication and in those <18 years old after
P-glycoprotein inhibitors such as amiodarone can tonsillectomy or adenoidectomy. Codeine should be
increase morphine exposure.21 avoided in children 12-18 years old who are obese or
have an increased risk of serious breathing problems
PREGNANCY — Opioid use during pregnancy has
and in breastfeeding women.29
been associated with preterm delivery, poor fetal
growth, stillbirth, birth defects (e.g., neural tube FENTANYL — Fentanyl is available in parenteral,
defects, congenital heart defects, gastroschisis), poor transdermal, intranasal, and oral transmucosal form-
physiological development, and neurodevelopmental ulations. It is FDA-approved only for use in opioid-
disorders.24,25 It can also lead to neonatal opioid tolerant patients. Fentanyl should be started only after
withdrawal syndrome. Opioid withdrawal during initial titration with a short-acting opioid.
pregnancy has been associated with spontaneous
Exposure of a fentanyl patch to an external heat source
abortion and premature labor. Pregnant women who
(e.g., a sauna, hot tub, or heating pad), increased exer-
are physically dependent on opioids should receive
tion, or high fever could increase release of the drug
buprenorphine or methadone.26
and the risk of respiratory depression.30 Deaths have
OVERDOSE REVERSAL – Administration of an opioid occurred in children following accidental exposure
antagonist can reverse severe respiratory depression to the patch. The FDA recommends disposing of the
due to an opioid overdose. patch by folding the sticky sides together and flushing
it down the toilet or by returning it to the pharmacy for
Naloxone is the opioid antagonist of choice. Intranasal
safe disposal.31
naloxone for rescue use should be offered to opioid-
treated patients who are at increased risk for overdose HYDROCODONE — Hydrocodone is an oral semi-
(e.g., patients taking ≥50 MME/day or concurrently synthetic opioid that is partly metabolized by CYP2D6
taking benzodiazepines, gabapentinoids, or other to hydromorphone. Immediate-release formulations
CNS depressants).27 Naloxone has a short half-life have been available for years in various fixed-dose
and repeated dosing may be needed, especially for combinations. Extended-release, single-entity hydro-
overdose with a long-acting or extended-release codone products are available for management
opioid agonist. of severe pain; they permit higher dosing than
immediate-release combination formulations.32,33
Nalmefene, which was recently returned to the market
in a generic injectable formulation, has a longer An oral, immediate-release, fixed-dose combination
duration of action than many opioid analgesics, and of benzhydrocodone, a prodrug of hydrocodone, and
it could precipitate a dangerously prolonged period of acetaminophen (Apadaz) is FDA-approved for short-
withdrawal in patients dependent on opioids. Data are term (<14 days) management of severe acute pain.
lacking on use of nalmefene for reversal of overdose
HYDROMORPHONE — A semi-synthetic opioid and
due to fentanyl or its analogues.28
a metabolite of hydrocodone, hydromorphone is
FULL OPIOID AGONISTS available in parenteral, rectal, and immediate- and
extended-release oral formulations.34 In an open-
CODEINE — Codeine is an oral opioid agonist with
label study in patients with chronic noncancer
a long history of use as an analgesic and cough
pain, once-daily hydromorphone was similar in
suppressant. It is a prodrug that is converted to
efficacy to twice-daily oxycodone and caused less
morphine by CYP2D6. Patients who are CYP2D6 poor
somnolence.35 The initial dosage of hydromorphone
metabolizers or are taking a CYP2D6 inhibitor (e.g.,
should be reduced in patients with moderate to
fluoxetine, paroxetine, bupropion) may be unable to
severe renal impairment.
convert codeine to morphine and may not experience
an analgesic effect.21 Patients who are CYP2D6 ultra- LEVORPHANOL — Oral levorphanol is used for treat-
rapid metabolizers convert codeine to higher-than- ment of chronic pain. It has a long half-life (16-18
usual levels of morphine, which may result in toxicity. hours) and can accumulate with repeated dosing.

The FDA has issued warnings about the use of MEPERIDINE — Meperidine should only be used for
codeine in children due to concerns about the risk short-term (24-48 hours) treatment of moderate to
of respiratory depression and death. The drug is severe acute pain. It is shorter-acting than morphine.
contraindicated for use in children <12 years old Meperidine has poor oral bioavailability, is highly

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Table 2. Some Oral/Transdermal Opioid Analgesics

Some Oral/Transdermal Usual Adult
Drug Formulations Initial Dosage1 Comments Cost2
Full Agonists
Codeine – generic 15, 30, 60 mg tabs 15-60 mg q4h ▶ Schedule II-V3 controlled substance $129.40
▶ Metabolized to morphine by CYP2D6
▶ MME conversion factor4: 0.155
▶ Also available in fixed-dose combinations
with acetaminophen
▶ Contraindicated in all children <12 years old
and in those <18 years old post-
adenoidectomy or tonsillectomy
Fentanyl ▶ Schedule II controlled substance
transdermal – generic 12, 25, 37.5, 50, 62.5, 75, See footnotes 6,7 ▶ MME conversion factor4: 162.40
87.5, 100 mcg/hr patches patch8: 2.4
transmucosal – tabs/lozenges9: 0.13
Actiq (Teva) 200, 400, 600, 800, 1200, 200 mcg nasal spray9: 0.16 87.4010
generic 1600 mcg transmucosal sublingual spray9: 0.18 12.2010
lozenges ▶ Also available parenterally
Fentora (Cephalon) 100, 200, 400, 600, 800 mcg 100 mcg ▶ Not recommended for opioid-naive patients 68.5010
generic buccal tabs ▶ Actiq, Fentora, Lazanda, and Subsys are 46.4010
Lazanda (West) 100, 400 mcg/100 mcL 100 mcg indicated only for breakthrough pain in 127.4010
nasal spray opioid-tolerant patients with cancer
Subsys (West) 100, 200, 400, 600, 800, 100 mcg ▶ Actiq may cause dental caries 76.6010
1200, 1600 mcg
sublingual spray
Hydrocodone – ▶ Schedule II controlled substance
extended-release – generic 10, 15, 20, 30, 40, 50 mg ER 10 mg q12h6,11 ▶ MME conversion factor4: 1 449.30
caps ▶ Immediate-release formulations only
Hysingla ER (Purdue)* 20, 30, 40, 60, 80, 100, 120 mg 20 mg q24h 6
available in fixed-dose combinations with 328.00
generic ER tabs acetaminophen, ibuprofen, homatropine, or 241.10
guaifenesin
Benzhydrocodone/ ▶ Schedule II controlled substance
acetaminophen – ▶ Prodrug of hydrocodone
Apadaz (KVK Tech) 4.08 mg, 6.12 mg, 8.16 mg/ 6.12 mg/325 mg ▶ Only available in a fixed-dose combination 31.20
generic 325 mg tabs q4-6h with acetaminophen 31.20
Hydromorphone – generic 2, 4, 8 mg tabs; 5 mg/5 mL 2 mg q6-8h ▶ Schedule II controlled substance 17.50
Dilaudid (Rhodes) PO soln ▶ MME conversion factor4: 4 279.30
extended-release – generic 8, 12, 16, 32 mg ER tabs See footnote 6 ▶ Also available in parenteral formulations, 218.4012
including a high-potency injectable, and as
a suppository
Levorphanol – generic 2, 3 mg tabs 2 mg q6-8h ▶ Schedule II controlled substance 3629.90
▶ MME conversion factor4: 11
▶ Accumulation may occur with chronic use
Meperidine – generic 50 mg tabs; 50 mg/5 mL 50 mg q3-4h ▶ Schedule II controlled substance 447.5013
PO soln ▶ MME conversion factor4: 0.1
▶ Also available parenterally
▶ Tissue irritation occurs with parenteral use
▶ Use should be limited to ≤48 hours
*FDA-approved as an abuse-deterrent formulation; ER = extended-release; MME = oral morphine milligram equivalent
1. Dosage for patients who are opioid-naive or opioid-nontolerant (products such as fentanyl are not recommended for such patients). In general, experts
recommend starting with the lowest available strength of an immediate-release opioid and titrating to effect; in opioid-naive patients, it would be reasonable
to start with 5-10 mg of morphine per dose or 20-30 mg per day, or its equivalent (see MME conversion factors above). For acute pain, an immediate-
release formulation of a full opioid agonist should be used as needed (i.e., not around the clock). Dosage adjustment for renal or hepatic impairment may be
necessary.
2. Approximate WAC for 30 days’ treatment at the lowest usual adult oral starting dosage or with the lowest available strength. 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. November 5, 2022. Reprinted with permission by First Databank, Inc. All rights reserved. ©2022. www.fdbhealth.com/
policies/drug-pricing-policy.
3. Single-agent codeine is a schedule II controlled substance; fixed-dose combinations containing acetaminophen are schedule III or V.
4. To convert the total daily dose of an opioid (except fentanyl: see footnotes 6 and 7) to MMEs, multiply its dose in mg/day by the conversion factor. The
conversion factor is an estimate and should not be used to determine the dosage for converting patients from one opioid to another. When converting
patients from one opioid to another, the new opioid is typically dosed substantially lower (25-50%) than the calculated dose in MMEs (CDC National Center
for Injury Prevention and Control. Available at: http://bit.ly/3g5Uz3E. Accessed November 21, 2022).

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Table 2. Some Oral/Transdermal Opioid Analgesics (continued)

Some Oral/Transdermal Usual Adult
Drug Formulations Initial Dosage1 Comments Cost2
Methadone – generic 5, 10 mg tabs; 5, 10 mg/5 mL 2.5-10 mg q8-12h 6
▶ Schedule II controlled substance $9.70
PO soln; 10 mg/mL PO ▶ MME conversion factor4: variable14
conc; 40 mg tabs for PO ▶ Also available parenterally
susp ▶ Accumulation may occur with chronic use
Morphine – generic 15, 30 mg tabs; 10 mg q4h ▶ Schedule II controlled substance 62.6015
10, 20, 100 mg/5 mL PO soln ▶ Also available for parenteral use and as
extended-release – a suppository
generic 15, 30, 60, 100, 200 mg ER tabs 15-30 mg q8-12h6 ▶ Taking ER caps with alcohol can result 31.70
MS Contin (Rhodes) in rapid release of morphine 252.60
generic 10, 20, 30, 50, 60, 80, 100 mg 30 mg q24h 6
▶ Maximum dose of multiphase ER caps 136.50
ER caps is 1600 mg because of renal toxicity of
multiphase – generic 30, 45, 60, 75, 90, 120 mg ER 30 mg q24h6 fumaric acid in the beads (chewing or 137.50
caps crushing the beads can be fatal)
Oxycodone – generic 5 mg caps; 5, 10, 15, 20, 30 mg 5-15 mg q4-6h ▶ Schedule II controlled substance 30.20
tabs; 5, 100 mg/5 mL PO soln ▶ MME conversion factor4: 1.5
Oxaydo (Egalet) 5, 7.5 mg tabs ▶ Also available in fixed-dose 1169.70
Roxybond (Daiichi Sankyo)* 5, 15, 30 mg tabs combinations with acetaminophen, 1311.60
extended-release – aspirin, or ibuprofen
OxyContin (Purdue)* 10, 15, 20, 30, 40, 60, 80 mg 10 mg q12h6 279.50
generic ER tabs 198.40
Xtampza ER (Collegium)* 9, 13.5, 18, 27, 36 mg ER caps 9 mg q12h6 355.00
Oxymorphone – generic 5, 10 mg tabs 5-15 mg q4-6h ▶ Schedule II controlled substance 112.80
extended-release – generic 5, 7.5, 10, 15, 20, 30, 40 mg ▶ MME conversion factor4: 3 218.50
ER tabs 5 mg q12h6 ▶ Also available parenterally
Full Agonist/Reuptake Inhibitors
Tapentadol – ▶ Schedule II controlled substance
Nucynta (Collegium) 50, 75, 100 mg tabs 50-100 mg q4-6h ▶ MME conversion factor4: 0.4 1060.30
extended-release – 50, 100, 150, 200, 250 mg ER 50 mg bid6 ▶ Fewer GI adverse effects, but similar
Nucynta ER tabs CNS effects compared to some other 570.90
opioid agonists
Tramadol – generic 50 mg tabs 50-100 mg q4-6h ▶ Schedule IV controlled substance 5.60
oral solution – generic 25 mg/5 mL oral soln ▶ Metabolized by CYP2D6 to a more 2378.40
extended-release – active metabolite
generic 100, 200, 300 mg ER tabs ▶ MME conversion factor4: 0.15 75.60
multiphase – generic 100, 200, 300 mg ER tabs 100 mg once/day 6
▶ 50 mg equivalent to codeine 60 mg; 45.50
biphasic – generic 100, 200, 300 mg ER caps16 100 mg comparable to aspirin 650 mg 229.60
ConZip (Vertical) plus codeine 60 mg 369.20
▶ Also available in fixed-dose
combinations with acetaminophen or
celecoxib
▶ Contraindicated in all children <12
years old and in those <18 years old
post-adenoidectomy or tonsillectomy
▶ Starting with 25 mg/day and slowly
titrating to usual dose over a few weeks
may improve tolerability
▶ Maximum dose is 400 mg/day for
immediate-release formulations and
300 mg/day for ER formulations
*FDA-approved as an abuse-deterrent formulation; ER = extended-release; MME = oral morphine milligram equivalent
5. MME conversion factor varies with CYP2D6 metabolizer status.
6. Starting dose determined by previous opioid dosage. Extended-release/long-acting formulations are generally not recommended for opioid-naive patients.
7. Not recommended for opioid-nontolerant patients. The recommended dosing interval is 72 hours. Some patients need to change the patch every 48 hours
to achieve adequate analgesia.
8. To convert the fentanyl patch to the MME dose/day, multiply the dose in mcg/hr by the conversion factor.
9. To convert fentanyl transmucosal products to MMEs, multiply the number of micrograms in a given unit by the conversion factor.
10. Cost for a single lozenge, tablet, or spray of the lowest available strength.
11. Concurrent use of alcohol can increase peak hydrocodone concentrations and should be avoided.
12. Cost of 30 8-mg tablets.
13. Cost for 2 days’ treatment.
14. The methadone conversion factor is 4 at doses of 1-20 mg/day, 8 at doses of 21-40 mg/day, 10 at doses at 41-60 mg/days, and 12 at doses of 61-80 mg/day.
15. Cost of 15-mg tabs.
16. 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 150 mg ER,
300 mg contains 50 mg IR and 250 mg ER.

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irritating to tissues when given subcutaneously, effects. Morphine-6-glucuronide maintains activity

and it can cause muscle fibrosis when given as an opioid agonist and could increase toxicity in
intramuscularly. persons with renal impairment.

Repeated doses of meperidine can lead to OLICERIDINE – An IV opioid, oliceridine (Olinvyk)

accumulation of normeperidine, a toxic metabolite couples the mu-opioid receptor preferentially to G
with a 15- to 30-hour half-life. Normeperidine can proteins, reducing activation of the beta-arrestin
cause dysphoria, irritability, tremor, myoclonus, and, pathway, which theoretically could decrease the risk
occasionally, seizures, particularly with postoperative of opioid adverse effects. In two 48-hour trials, it was
patient-controlled analgesia, or in elderly patients or not superior to morphine in relieving moderate to
those with impaired renal function. severe acute postoperative pain. Oliceridine appears
to cause less GI toxicity than morphine, but its
METHADONE — Methadone is available orally and
maximum daily dose is limited by a risk of QT-interval
parenterally for treatment of chronic pain and orally
prolongation, and it is expensive.39
for maintenance treatment of opioid use disorder.9
In one study, methadone was similar in efficacy to OXYCODONE — Oxycodone, a semi-synthetic opioid,
long-acting morphine for first-line treatment of is only available in oral formulations in the US. It is
cancer pain.36 frequently used in combination with acetaminophen
for treatment of acute pain. A long-acting formulation
The plasma half-life of methadone is variable
is commonly used for treatment of chronic pain.
and does not correlate with the duration of
analgesia; close monitoring is required during the OXYMORPHONE — A metabolite of oxycodone, oxy-
titration period because repeated doses can lead morphone is available in parenteral and immediate-
to accumulation, CNS depression, and death. In and extended-release oral formulations.40 Opana ER,
comparison to other opioids, use of methadone for an oral extended-release formulation of oxymorphone,
pain relief has been associated with a higher risk of was removed from the market because of a high risk
death from overdose.37 of abuse41; generic formulations of oral extended-
release oxymorphone remain available.
In addition to being a mu-agonist, methadone is
also an NMDA (N-methyl-D-aspartate) receptor ABUSE-DETERRENT OPIOIDS — Several full-
antagonist. NMDA receptor antagonism can agonist opioids are available in “abuse-deterrent”
be helpful when other opioids are ineffective, formulations (see Table 2). These formulations have
particularly in treating neuropathic pain. Switching one or more properties that make their intentional
from another opioid agonist to methadone should nontherapeutic use more difficult, less attractive, or
be done cautiously by an experienced clinician; less rewarding. No studies comparing the relative
the equianalgesic dose of methadone is not well safety of these products are available. Whether using
established in opioid-tolerant patients. them actually reduces overall opioid abuse remains
to be established. No opioid formulation prevents
Methadone has no active metabolites, which may consumption of a large number of intact dosage
be advantageous in patients with renal impairment. units, the most common method of abuse.42-44
Dose-related QT-interval prolongation, torsades de
pointes, and death have been reported.38 FULL AGONIST/REUPTAKE INHIBITORS

TAPENTADOL — Tapentadol is an opioid agonist

MORPHINE — Morphine is available in parenteral,
and a norepinephrine reuptake inhibitor. It is
rectal, and immediate- and extended-release oral
available in immediate- and extended-release oral
formulations. After oral administration, morphine
formulations.45 The extended-release formulation
undergoes extensive first-pass metabolism, resulting
appears to provide analgesic efficacy similar to that
in a bioavailability of about 35%. It commonly causes
of extended-release oxycodone with fewer GI adverse
nausea, vomiting, and constipation. Morphine should
effects.46 Tapentadol is contraindicated for use with
be used with caution in patients with severe renal
or within 14 days of taking an MAO inhibitor.
impairment because accumulation of its metabolites
can occur. Increased concentrations of morphine- TRAMADOL — Tramadol is an oral, centrally-
3-glucuronide, a neurotoxic metabolite, can cause acting opioid agonist that inhibits reuptake of
agitation, confusion, delirium, and other adverse norepinephrine and serotonin. It is metabolized

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by CYP2D6 to a metabolite that is 2-4 times chronic back pain.50,51 Because of the low maximum
more active than the parent drug; CYP2D6 poor dose of the patch (20 mcg/hr), it is not useful for
metabolizers and patients taking a CYP2D6 treatment of severe cancer pain. Patients maintained
inhibitor may not experience an analgesic effect.21 on transdermal buprenorphine may require higher-
Tramadol is available alone and in combination with than-normal doses of full opioid agonists during
acetaminophen and with celecoxib (Seglentis).47 and for up to 48 hours following discontinuation of
The combination of tramadol and acetaminophen the patch.
for treatment of chronic pain is comparable in
Buprenorphine has a ceiling on its respiratory
efficacy to that of oxycodone plus acetaminophen.
depressant effect and a lower abuse potential than
The need for slow dose titration to decrease nausea
full opioid agonists. Nausea, headache, dizziness,
and improve tolerability when initiating tramadol
and somnolence are common adverse effects, and
limits its use for treatment of acute pain. Tramadol
it can precipitate withdrawal in persons taking full
may be effective for treatment of neuropathic pain,
opioid agonists.
but the supporting evidence is weak.48
MIXED AGONIST/ANTAGONISTS
Seizures have been reported with tramadol; patients
with a history of seizures and those who are also The mixed opioid agonist/antagonists pentazocine,
taking a tricyclic antidepressant, an SSRI, an MAO butorphanol, and nalbuphine all have a ceiling on
inhibitor, other opioids, or an antipsychotic drug may their analgesic effects and can precipitate withdrawal
be at increased risk. Administration of naloxone for symptoms in patients physically dependent on full
an overdose of tramadol may increase seizure risk. opioid agonists. These drugs are less likely than full
Concentrations of the active metabolite of tramadol agonists to cause physical dependence, but none is
may be higher in CYP2D6 ultra-rapid metabolizers, entirely free of dependence liability. ■
resulting in a higher incidence of adverse effects.
Concurrent use of tramadol with drugs that inhibit
Additional Content Available Online
CYP2D6 or 3A4 can increase tramadol levels and
Comparison Table: Some Oral/Transdermal Opioid Analgesics
seizure risk.21 http://medicalletter.org/TML-article-1665b
Hyponatremia has been reported with use of tramadol,
particularly during the first week of treatment in
1. D Dowell et al. CDC clinical practice guideline for prescribing
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Rockville (MD): Agency for Healthcare Research and
is contraindicated for use in children <12 years old
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for any indication and in those <18 years old after Available at: http://bit.ly/3UCZzvR. Accessed November
tonsillectomy or adenoidectomy. Use of tramadol 21, 2022.
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Vol. 64 (1665) December 12, 2022

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26.Substance Abuse and Mental Health Services Administration.
Clinical guidance for treating pregnant and parenting women
with opioid use disorder and their infants. HHS Publication
No. (SMA) 18-5054. Rockville, MD: 2018. Available at: http:// The Medical Letter Site License
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Issue 1665 Post-Activity Questions

(Correspond to questions #111-120 in Comprehensive Activity #87, available January 2023)

Opioids for Pain 6. CYP2D6 inhibitors can decrease the analgesic effect of:
a. morphine
1. Tolerance usually develops rapidly to most effects of b. meperidine
opioids, but not to: c. codeine
a. sedation d. all of the above
b. constipation
c. analgesia 7. Methadone:
d. emesis a. has been associated with a lower risk of death from
overdose compared to other opioids
2. Use of a drug that inhibits CYP3A4 can increase serum b. is converted to an active metabolite that can
concentrations of: accumulate in patients with renal impairment
a. fentanyl c. can prolong the QT interval
b. hydrocodone d. all of the above
c. tramadol
d. all of the above 8. Oral morphine has a bioavailability of about:
a. 20%
3. Which of the following is recommended for use in a b. 35%
pregnant woman who is physically dependent on opioids? c. 60%
a. tramadol d. 85%
b. codeine
c. methadone 9. Tramadol:
d. fentanyl a. inhibits norepinephrine and serotonin reuptake
b. can cause seizures
4. Patients taking ≥50 MME/day of an opioid should be c. is converted to a more active metabolite by CYP2D6
offered which of the following for rescue use? d. all of the above
a. injectable nalmefene
b. injectable epinephrine 10. Which of the following would be most appropriate for an
c. intranasal naloxone otherwise healthy 17-year-old male with severe post-
d. oral buprenorphine tonsillectomy pain despite treatment with an NSAID?
a. oral immediate-release tramadol 50 mg taken q4h
5. Codeine is: around the clock
a. a prodrug of morphine b. oral immediate-release oxycodone 5 mg taken q6h as
b. contraindicated for use in children <12 years old needed
c. not recommended for use in women who are c. oral extended-release oxycodone 20 mg taken q8h
breastfeeding around the clock
d. all of the above d. transdermal fentanyl 75 mcg/hr patches applied q48h

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