Cases & Commentaries

Miscalculated Risk

Commentary By Scott A. Strassels, PharmD, PhD, BCPS

The Case

A healthy 36-year-old man was admitted to a
teaching hospital for acute low back strain after lifting his
2-week-old infant. He received Vicodin (hydrocodone and
acetaminophen) on an "as needed" basis. After 2 days, the intern
was instructed to switch the patient to long-acting oral morphine
in anticipation of discharge. After the first dose of MS Contin
(controlled-release oral morphine), the patient was noted to be
somnolent; 3 hours later, he was in respiratory distress. He was
intubated and transferred to the intensive care unit. The ICU team
evaluated his recent analgesic use and determined that he had
received a dose of MS Contin that far exceeded his previous Vicodin
requirement. The patient subsequently developed acute respiratory
distress syndrome (ARDS) and sepsis, presumably related to
aspiration. He remained in the ICU for 2 weeks and required
pressors for blood pressure management. Eventually, the patient
recovered fully and was discharged home.

The Commentary

High alert medications, opioids, and
respiratory depression. As this case illustrates, oral opioids
are high-risk drugs worthy of serious consideration when evaluating
medication safety from an institutional perspective. Respiratory
depression, the most serious opioid-related adverse effect, is most
common within several days of beginning scheduled therapy and when
converting from one regimen to another.(1,2) As in this case, somnolence often precedes
hypoventilation; thus, vigilant monitoring for sedation (in
addition to monitoring of respiratory status) is critically
important in the routine care of patients receiving opioid
therapy.

The error in this case was attributed to
therapeutic conversion using a nonequivalent analgesic dose.
Whether the error was caused by a calculation mistake when
converting from Vicodin (hydrocodone and acetaminophen) to MS
Contin (controlled-release oral morphine), a misunderstanding
regarding the relative potencies of the two products, or some other
cause, is not known. Regardless, it appears that there was a lack
of understanding regarding the appropriate use of long-acting
opiates, as well as a failure on the part of the pharmacist and
nurse to appreciate the excessive dose relative to the patient's
prior use of Vicodin. The long-acting opioids (fentanyl transdermal
system [Duragesic], controlled-release morphine [MS Contin],
controlled-release oxycodone [OxyContin], extended-release morphine
[Avinza, Kadian], and methadone) are generally reserved for use in
persons who are not opioid-naïve, whose analgesic requirements
are stable, and who are expected to need opioid analgesia for an
extended period of time. In this case, if the patient's pain was
not well controlled, use of a more potent immediate-release opioid
would have been a reasonable step before switching to a long-acting
drug.

Other types of errors reported in conjunction
with use of opioids include name confusion, inappropriate use of
adjunct medications, and use of a confusing array of overlapping
analgesic regimens.(3-6)
Reports of name confusion include using opium tincture
(which contains 10 mg/mL of morphine) in place of camphorated
tincture of opium
(also known as paregoric), which contains 0.4
mg/mL of morphine.(5)
Hydromorphone, meperidine, and morphine have also been erroneously
interchanged, as have drugs with similar-sounding brand names, like
Avinza (morphine sulfate extended release), Evista (raloxifene
hydrochloride, a drug to prevent osteoporosis), and Invanz
(ertapenem sodium, an antibiotic), or Roxanol (20 mg of morphine
per mL), Roxicet (oxycodone with acetaminophen), and Roxicodone
Intensol (20 mg of oxycodone per mL).(6) Inappropriate use of promethazine or hydroxyzine may
contribute to sedation and other adverse effects without enhancing
analgesia.(3)
Another potential problem occurs when prescribers order different
analgesic regimens depending on the patient's self-assessment of
pain severity (eg, acetaminophen, 650 mg by mouth every 4 hours for
pain scale ratings of 1-3; acetaminophen with codeine, 30 mg by
mouth every 4 hours for pain ratings of 4-6; morphine, 2 mg IV
every 3 hours for pain ratings of 7-8; and so on).(3) Inadvertent acetaminophen overdoses are another
important concern, since this analgesic is present in many
combination products.(7) The
total amount of acetaminophen from all sources should not exceed 4
grams per day; lower ceiling doses (2 grams per day or less) are
recommended in alcoholic persons and individuals with diminished
hepatic or renal function.

Equianalgesic conversion. Changing from
one opioid analgesic to an alternative drug may be necessary when
pain persists despite increasing doses, when a patient develops an
adverse event (eg, an allergic reaction or intolerable side
effect), when converting between routes of administration, or when
changing between long-acting and short-acting agents based on the
goals of pain management. Clinicians must understand the basic
concepts of equianalgesic conversion. Importantly, conversions are
not exact, and cross tolerance between opioids is incomplete. For
these reasons, the calculated dose of the new opioid is often
reduced by 25%-50% depending on how well pain is controlled. In
addition, rescue medications must be made available for
breakthrough pain.

To calculate an equianalgesic dose, the following
steps should be followed:

  • First, add up the patient's total
    24-hour analgesic requirement, including all doses for breakthrough
    pain.(1,2)
  • Second, convert that total amount to the
    drug and route desired using a conversion table, such as the
    Table below.
  • Third, divide the total 24-hour dose of
    the new drug by the number of daily doses to be administered. The
    duration of action values in the Table are helpful in this regard.
  • Fourth, consider reducing the calculated
    dose of the new drug by 25%-50%. The specific reduction often
    depends on how well the patient's pain is controlled. For example,
    if pain is well controlled, the dose of the new drug may be reduced
    by 50%, and liberal doses for breakthrough pain would be
    ordered.
  • Finally, calculate a rescue dose for
    breakthrough pain. This amount is generally up to 20% of the total
    daily opioid dose, given every 3 to 4 hours as needed.

As an example, assume that a person has required
54 mg of IV morphine during the previous 24 hours and that a switch
to immediate-release oxycodone is planned in preparation for
hospital discharge. Using the Table, 10 mg of IV morphine is roughly equivalent to 20
mg of oral oxycodone. Multiplying 54 mg by the dose ratio from the
conversion table (20/10, or 2), the total expected 24-hour dose of
oxycodone is 108 mg. Immediate-release oxycodone is dosed every 2
to 4 hours. At the full conversion rate, two options for dosing are
9 mg of oxycodone every 2 hours or 18 mg of oxycodone every 4
hours. These amounts would likely be rounded to 10 or 20 mg per
dose (depending on whether the 2-hour or 4-hour dosing interval is
chosen) to take advantage of 5-mg tablets. If this expected dose is
reduced by 50% to account for possible incomplete cross-tolerance,
dosing schedules of 5 mg every 2 hours or 10 mg every 4 hours could
be recommended. The dose for breakthrough pain would be up to 20%
of the daily dose (about 10 mg). It is important to note that other
analgesic conversion methods are available and that equianalgesic
doses may differ depending on which conversion method is
used.(8,9)
In addition, equianalgesic dose ratios different from those shown
in the Table may be appropriate for patients on long-term
opioid therapy.(10)

Preventing opioid errors. Strategies to
prevent opioid errors are not substantially different from those
used for other types of medication errors, with a few exceptions.
For example, a new order for a long-acting opioid should be
accompanied by a check to determine whether the person is
opioid-naïve. Similarly, equianalgesic requirements can be
calculated when the route of administration is changed or when a
more potent drug is started. Computerized prescriber order
entry (CPOE) is a promising technology for its potential to
reduce medication errors.(11)
CPOE might improve analgesic safety by preventing prescribers from
ordering drugs not on the institution formulary or alerting the
prescriber that use of a drug for a given patient is not
recommended. Also, equianalgesic conversion algorithms could be
programmed into CPOE software to help prescribers choose drugs and
doses. Although this tool could be potentially useful, it is
important to acknowledge that opioid dosing is very flexible and
that a single algorithm would likely not be appropriate for all
clinical situations. In this regard, another important system
approach to enhance analgesic safety is to ensure that prescribers,
nurses, and pharmacists are all comfortable with equianalgesic
calculation methods, independent of any computerized
system.

Take-Home Points

  • Respiratory depression is a potentially
    serious, but uncommon, adverse effect of opioid analgesics. Fear of
    respiratory depression should not interfere with provision of
    appropriate analgesia.
  • Sedation typically precedes respiratory
    depression; thus, monitoring for sedation should be a routine part
    of caring for persons who receive opioid analgesics, particularly
    when starting treatment or changing doses.
  • In general, use of long-acting opioid
    analgesics should be reserved for persons who are opioid-tolerant,
    who are expected to require opioid-level analgesia for an extended
    period, and whose analgesic requirements are relatively
    stable.
  • Equianalgesic conversion methods are
    easily used, but the results are estimates. Reducing the
    "equipotent" dose of the new analgesic by up to 50% and allowing
    for liberal rescue doses to treat breakthrough pain may help avoid
    opioid overdoses. Importantly, patients whose pain is not
    well-controlled at the time of drug conversion may not need to have
    their dose decreased, or may even require an increased dose.
  • Nurses and pharmacists should actively
    evaluate changes in prescribed opioid regimens and question orders
    that appear to represent a significant increase or decrease in
    dosage compared with a patient's prior stable analgesic
    requirement.

Scott A. Strassels, PharmD, PhD, BCPS
Assistant Professor, Division of Pharmacy Practice
University of Texas at Austin

References

1. Pasero C, Portenoy RK, McCaffery M. Opioid
analgesics. In: McCaffery M, Pasero C, eds. Pain: Clinical Manual.
2nd ed. St. Louis, MO: Mosby; 1999:161-299.

2. Ashburn MA, Lipman AG, Carr D, et al.
Principles of Analgesic Use in the Treatment of Acute Pain and
Cancer Pain. 5th ed. Glenview, IL: American Pain Society;
2003.

3. Pain scales don't weigh every risk. ISMP
Medication Safety Alert! Acute Care Edition. July 24, 2002.
Available at: http://www.ismp.org/Newsletters/acutecare/articles/20020724.asp.
Accessed July 31, 2006.

4. Special Edition: Drug Advisory. Confusion
between opioid analgesics results in deaths. USP Quality Review No.
46. February 1995. Available at:
http://www.usp.org/patientSafety/newsletters/qualityReview/qr461995-02-01a.html
.
Accessed July 31, 2006.

5. Opium. Facts & Comparisons 4.0. Available
at:
http://online.factsandcomparisons.com/MonoDisp.aspx?monoID=fandc-hcp11543&book=dfc
.
Accessed 4/14/2006.

6. Action may be necessary to prevent confusion
between Roxane's oral liquid opiate products. ISMP Medication
Safety Alert! Acute Care Edition. December 18, 1996. Available at:
http://www.ismp.org/Newsletters/acutecare/articles/19961218.asp.
Accessed July 31, 2006.

7. Acetaminophen (N-Acetyl-P-Aminophenol, APAP).
Facts & Comparisons 4.0. Available at:
http://online.factsandcomparisons.com/MonoDisp.aspx?monoID=fandc-hcp13078&&book=dfc
.
Accessed July 31, 2006.

8. Ready LB, Edwards WT, eds. The Management of
Acute Pain: A Practical Guide. Seattle, WA: International
Association for the Study of Pain; 1992.

9. Anderson R, Saiers JH, Abram S, Schlicht C.
Accuracy in equianalgesic dosing: conversion dilemmas. J Pain
Symptom Manage. 2001;21:397-406.
[go to PubMed]

10. Souter KJ, Fitzgibbon D. Equianalgesic dose
guidelines for long-term opioid use: theoretical and practical
considerations. Seminars in Anesthesia, Perioperative Medicine and
Pain. 2004;23:271-280.

11. Kilbridge PM, Welelob EM, Classen DC.
Development of the Leapfrog methodology for evaluating hospital
implemented inpatient computerized physician order entry systems.
Qual Saf Health Care. 2006;15:81-84.
[go to PubMed]

Table

Table. Opioid equianalgesic dosage
conversion

Drug Parenteral (mg) Oral (mg) Duration of action (hr)*
Codeine phosphate or sulfate 120 200 3-4
Hydromorphone hydrochloride 1.5 7.5 2-4
Meperidine hydrochloride 75 300 2-4
Methadone hydrochloride† 5 10 6-8
Morphine sulfate 10 30 2-4
Oxycodone hydrochloride NA 20 2-4

*Values reflect immediate-release products.

†Substantial decreases in doses may be
needed when converting to methadone (~90%) because of the drug's
long elimination half-life and N-methyl-d-aspartate-receptor
activity.