JOURNAL OF PALLIATIVE MEDICINE
`Volume 2, Number 2, 1999
`Mary Ann Liebert, Inc.
`
`Review Article
`
`Opioid Equianalgesic Calculations
`
`DEBRA B. GORDON, R.N., M.S.,l KAREN K. STEVENSON, R.N., M.S.,2
`JULIANN GRIFFIE, R.N., M.S.N.,3 SANDY MUCHKA, R.N., M.S.,3
`CATHY RAPP, R.N., M.S.,4 and KATE FORD-ROBERTS, R.N., B.S.N.l
`
`ABSTRACT
`
`Among the knowledge required by healthcare professionals to manage pain is an under(cid:173)
`standing of the differences between opioid agents and formulations. As the list of new opi(cid:173)
`oid formulations continues to grow, it is increasingly important that clinicians understand
`the basic pharmacology of these analgesics and how to calculate equianalgesic doses. Ad(cid:173)
`ministering an equianalgesic dose increases the likelihood that the transition to another opi(cid:173)
`oid or route will be tolerated without loss of pain control or excessive side effects. Although
`calculation of equianalgesic doses requires relatively simple mathematical skills, few clini(cid:173)
`cians are prepared to compute them. The purpose of this article is to provide a basic review
`of the pharmacology of opioids, explain how to calculate an equianalgesic dose, and briefly
`describe some of the current controversies of the relative potencies of opioids listed in
`equianalgesic tables.
`
`INTRODUCTION
`
`I NADEQUATE PAIN CONTROL continues to be a
`
`major healthcare problem. Despite the fact
`that most pain can be controlled with relatively
`simple means (eg, oral analgesics), clinical
`studies continue to report inadequate care.l-3
`Among the most frequently cited reasons for
`undertreatment are knowledge deficits of
`healthcare providers.4-6 Although pharmaco(cid:173)
`logic treatment is the cornerstone of pain man(cid:173)
`agement, many clinicians fear and misunder(cid:173)
`stand opioid analgesics. Knowledge deficits
`surrounding opioids include risk of tolerance
`
`and addiction, drug choice, appropriate routes
`of administration, calculation of equianalgesic
`doses, titration of doses, and management of
`side effects.
`Clearly, pain management is an interdisci(cid:173)
`plinary process, however many have recog(cid:173)
`nized the unique and central role of the
`nurse?'8 The nurse is the key link in assess(cid:173)
`ment, administration of interventions, and
`evaluation of the impact of interventions on an
`individual. Nurses make significant contribu(cid:173)
`tions to facilitate communication and decision
`making in pain management. To do so, nurses
`must process increasingly sophisticated skills
`
`1University of Wisconsin Hospital and Clinics, Madison, Wisconsin.
`2Wisconsin Cancer Pain Initiative, Madison, Wisconsin.
`3Froedtert Hospital-East, Milwaukee, Wisconsin.
`4St. Joseph's Hospital, Milwaukee, Wisconsin.
`
`209
`
`

`

`210
`
`in all areas of pain management, including the
`choice of analgesic, dose, route, and appropri(cid:173)
`ate dosing interval. However, when presented
`with common conversion scenarios, 56°/o-73°/o
`of 2135 nurses surveyed provided answers that
`would result in either under or over treatment.9
`In a separate study, one-third of nurses, who
`were identified as caring for patients with can(cid:173)
`cer, were unable to calculate equianalgesic
`doses in spite of having access to an equianal(cid:173)
`gesic table. 10
`Although the list of available opioids has re(cid:173)
`mained relatively constant, the array of opioid
`formulations continues to grow. Whether for
`convenience or out of medical necessity, many
`patients need to be converted between differ(cid:173)
`ent routes and opioids. Nurses are in a unique
`position to help determine the appropriate for(cid:173)
`mulation, route, and dosage to meet an indi(cid:173)
`vidual patient's needs. Calculation opioid
`equianalgesic conversions is an important task
`for nurses, in part, because other healthcare
`providers may be unprepared to do so. The
`purpose of this article is to explain equianal(cid:173)
`gesia and provide a resource to assist clinicians
`in learning how to calculate opioid route or
`drug conversions. Current controversies in
`equianalgesia are also examined.
`
`OPIOID PHARMACOLOGY
`
`Opioids are the drugs of choice for the treat(cid:173)
`ment of moderate to severe nociceptive pain.
`Opioid analgesics are classified as pure ago(cid:173)
`nists, mixed agonist-antagonists, or antago(cid:173)
`nists, depending on which receptors they bind
`to and their activity at that receptor site.2 Pure
`agonists are most commonly used to treat pain
`because they produce a maximal biologic re(cid:173)
`sponse, whereas the mixed agonist-antagonists
`produce a submaximal response.l1 Pure ago(cid:173)
`nists exhibit a steep dose-response curve.12 In
`practical terms, this means as the dose is in(cid:173)
`creased, so is the amount of pain relief ob(cid:173)
`tained. When compared with pure agonists,
`mixed agonist-antagonists (buprenorphine, bu(cid:173)
`torphanol, nalbuphine, pentazocine, dexocine)
`exhibit a "ceiling effect." This means that above
`a certain dose there is no more gain in analge(cid:173)
`sia. Agonist-antagonists can reduce the effect
`
`GORDON ET AL.
`
`of a pure agonist, and in some cases even pre(cid:173)
`cipitate withdrawal symptoms when adminis(cid:173)
`tered concomitantly with pure agonists. An(cid:173)
`tagonists (naloxone) reverse the effects of
`agonists.
`The most commonly used pure agonists in(cid:173)
`clude morphme, hydromorphone, oxycodone,
`hydrocodone, methadone, levorphanol, and
`fentanyl. Of these, morphine is the most widely
`available and often considered the prototype
`because of its well characterized pharmacoki(cid:173)
`netics and pharmacodynamics. Pharmacoki(cid:173)
`netics refers to the study of the absorption, dis(cid:173)
`tribution, biotransformation, and excretion of
`drugs. 13 Pharmacodynamics is the study of the
`biochemical effects of drugs and their mecha(cid:173)
`nisms of action.13 In other words, pharmacoki(cid:173)
`netics is what the body does to the drug, and
`pharmacodynamics is what the drug does to
`the body. Although all opioid agonists produce
`pharmacologic effects similar to morphine,
`their pharmacokinetics differ widely.
`Important concepts of opioid pharmacody(cid:173)
`namics include potency and equianalgesia. Po(cid:173)
`tency refers to the intensity of analgesic effect
`for a given dose, and is based on access to the
`receptor and binding affinity at the receptor
`site.l 1 Apparent differences in potency of vari(cid:173)
`ous opioids are primarily the result of physio(cid:173)
`chemical and pharmacokinetic differences of
`individual opioids. For example, fentanyl is
`more potent than morphine (administered by
`the same route) because the dose (milligrams)
`of morphine required to achieve the same anal(cid:173)
`gesia as fentanyl is 100 times the (milligram)
`fentanyl dose. Potency is a relatively unimpor(cid:173)
`tant factor except in situations where limited
`volume is an issue, such as in subcutaneous or
`intrathechal infusions. Potency is not the same
`as the efficacy of a drug, which instead refers
`to the maximal effect that can be produced by
`a drug. With the exception of codeine and dex(cid:173)
`tropropoxyphene, most of the pure agonist
`opioids are considered to have equal maximal
`efficacy, that is, they are equally effective to
`control moderate to severe pain. 12
`Although the general side-effect profile of
`pure agonists is fairly similar, there is consid(cid:173)
`erable variation among patients' responses to
`these drugs. Clinicians should understand that
`some patients will require trials of different
`
`

`

`OPIOID EQUIANALGESIC CALCULATIONS
`
`opioids before finding an effective and well-tol(cid:173)
`erated drug. Clinicians may need to switch opi(cid:173)
`oids to improve pain control, reduce opioid
`toxicity or side effects, provide a more conve(cid:173)
`nient treatment regimen for the patient, or to
`reduce the invasiveness of therapy. 15,16 It is also
`recognized that many patients may require use
`of multiple routes as they near end of life. In a
`study of 90 advanced cancer patients treated by
`the Supportive Care Program at Memorial
`Sloan Kettering Cancer Hospital, more than
`half required use of 2 or more routes for opi(cid:173)
`oid administration, necessitating equianalgesic
`substitution.17,18
`Two doses are considered equianalgesic if
`they provide approximately the same amount
`of pain relief. Because opioids differ from one
`another in potency (how much relief they
`provide per milligram), it is important to
`have some point of reference in comparing
`these drugs. An equianalgesic table provides
`a listing of opioids at doses that produce
`approximately the same amount of analgesia.
`Equianalgesic tables can be helpful when
`switching from one opioid to another, or when
`changing between the oral and parenteral
`route, so that the same amount of analgesia can
`be maintained. Equianalgesic dose calculation
`provides a basis for selecting the appropriate
`starting dose when switching opioids or chang(cid:173)
`ing routes.14 Erroneous equianalgesic calcula(cid:173)
`tions can lead to needless suffering for patients,
`either from unrelieved pain, or from unneces(cid:173)
`sary toxicity.
`Equianalgesic tables provide listings of opi(cid:173)
`oid doses that produce approximately the same
`amount of analgesia based on bioavailability
`and potency. The bioavailability is the percent
`of drug that ends up in systemic circulation,
`therefore, intravenous drugs are considered to
`have 100°/o bioavailability. Bioavailability of
`orally administered opioids is generally one(cid:173)
`third to one-fifth that of IV administration due
`to the first-pass effect.13 That is, drugs taken by
`the oral route must first be absorbed through
`the gut and pass through the liver where much
`of the dose may be inactivated by biochemical
`processes that change a portion of the drug into
`different product metabolites. Because the
`bioavailability of parenterally administered
`drugs is different than oral formulations, the
`
`211
`
`dosage must be changed when the route is
`switched. Equianalgesic tables compare only
`the agonists, and the oral and parenteral
`(intravenous/ subcutaneous I intramuscular)
`routes. When opioids are administered by
`other routes, such as topically, epidurally or in(cid:173)
`trathecally, other factors must be considered
`such as opioid lipid solubility and the proxim(cid:173)
`ity of drug delivery to. opioid receptors.
`
`THE EQUIANALGESIC TABLE
`
`The first column of Table 1 lists the generic
`and trade names of the most common opioid
`agonists. The second column lists the equianal(cid:173)
`gesic parenteral (intramuscular or subcuta(cid:173)
`neous or intravenous) doses. The third column
`lists the equianalgesic oral doses, followed by
`columns for parenteral:oral ratio, and duration
`of action. The duration of action is the same for
`the parenteral and (short acting) oral formula(cid:173)
`tions. All doses listed on the table are consid(cid:173)
`ered approximately equal in analgesic effect.
`For example, 7.5 mg of oral hydromorphone is
`approximately equal to 10 mg of parenteral
`morphine in terms of providing pain relief.
`It is critical to remember that the doses are
`approximate and most are based on single dose
`studies.19 The doses are to be used only as a
`guide for calculating an initial conversion dose.
`The relative potency of some opioids, such as
`methadone and levorophanol, may increase
`with repetitive dosing. 11 Doses listed on the
`table were selected for the purpose of conve(cid:173)
`nience to make comparisons easy. Clinicians
`may erroneously assume the doses listed are
`recommended starting doses. This is not the
`case. They suggest the ratio or proportion to
`use when calculating a new dose.
`Patients can become tolerant to the analgesic
`and side effects of a given opioid, but not ex(cid:173)
`hibit the same tolerance to another opioid. This
`is called incomplete cross-tolerance; meaning
`caution must be used when an equianalgesic
`dose of a different opioid is administered.
`When switching to a different opioid, it is rec(cid:173)
`ommended that only one-third to one-half of
`the calculated equianalgesic dose sho~ld be ad(cid:173)
`ministered initially, particularly when pain is
`being controlled by the current drug.2 How-
`
`

`

`212
`
`Drug
`
`Morphine
`Hydromorphone
`(Dilaudid)
`Oxymorphone
`(Numorphone)
`Oxycodone0
`(Roxicodone, Roxicet, Percocet)
`Codeine
`Hydrocodone00
`(Vicodin, Vicoprofen, Lortab, Lorcet)
`Propoxyphene
`(Wygesic, Darvocet)
`Meperidine
`(Demerol)
`Levorphanol
`(Levo-Dromoran)
`Methadone
`(Dolophine)
`Fentanyl
`(Sublimaze) (Duragesic")
`
`TABLE 1. EQUIANALGESIC TABLE
`
`Parenteral
`
`10
`1.5
`
`1
`
`Not available
`in U.S.
`130
`
`75
`
`2
`
`10
`
`0.1"
`
`PO
`
`30
`7.5
`
`10
`
`20-30
`
`200NA
`30NA
`
`NA*
`
`300**
`
`4
`
`3-5***
`
`GORDON ET AL.
`
`Parenteral: PO ratio
`
`Duration of action
`(hr)
`
`1:3
`1:5
`
`1:10
`
`1:1.5
`
`1:4
`
`1:2
`
`3-4
`3-4
`
`3-4
`
`3-4
`
`3-4
`3-4
`
`4-6
`
`3-4
`
`3-4
`
`4-12
`
`1-3""
`
`Adapted from Cherny NI. Drugs 199643; 51:713-737; Pasero C, Portenoy R, McCaffery M. Pain: Clinical Manual.
`St. Louis, Mosby 199914; UW Health Pain Reference Card 4th ED, UW Board of Regents, 1998.
`Duration of action based on use of short acting formulations.
`NA, equianalgesic data unavailable. Codeine doses should not exceed 1.5 mg/kg because of an increased incidence
`of side effects with higher doses.
`0 These products contain 5 mg oxycodone with some combination of aspirin or acetaminophen.
`00These products contain 5, 7.5, or 10 mg of hydrocodone with some combination of aspirin, acetaminophen, or
`ibuprofen.
`*Long half-life. Accumulation of toxic metabolite (norpropoxyphene) with repetitive dosing. Inappropriate for use
`in the elderly.
`**Avoid multiple dosing with meperidine (no more than 48 hrs or at doses greater than 600 mg/24 hours).
`Accumulation of toxic metabolite normeperidine (half-life 12-16 hours) can lead to CNS excitability and convulsions.
`Contraindicated in patients receiving MAO inhibitors.
`***Although many equianalgesic tables list 20 mg as the PO oral methadone equianalgesic dose, recent data
`suggest methadone is much more potent with repetitive dosing. Ratios between PO morphine and PO methadone
`may range from 4-14:1.
`"Transdermal fentanyl100 p,g/hr is approximately equivalent to 2-4 mg/hr of IV morphine. A conversion factor
`for transdermal fentanyl that can be used for equianalgesic calculation is 17 p,g/hr. Roughly, the dose of transdermal
`fentanyl in p,g/hr is approximately one-half of the 24-hour dose of oral morphine.
`.
`/\/\Single dose data. Continual intravenous infusion produces lipid accumulation and prolonged terminal excretion.
`
`ever if pain is not controlled, a clinician may
`decide to administer the new opioid at the cal(cid:173)
`culated equianalgesic dose or at a percentage
`increase (25°/o-100°/o) based on the severity of
`pain. Information other than the equianalgesic
`calculation should be taken into consideration
`in determining the new dose, including the
`drug's half-life, bioavailability, drug interac(cid:173)
`tions, hepatic and renal clearance, the patient's
`type of pain and prior opioid exposure.20 As al(cid:173)
`ways, individual patient response must be ob(cid:173)
`served, and doses and intervals between doses
`need to be titrated according to the patient's
`response.
`
`It is important to recognize that the way in
`which a drug is administered ( eg, single dose,
`divided doses, or continuous dosing) is deter(cid:173)
`mined by the route, product formulation, clin(cid:173)
`ical pharmacology of the drug, and by the
`clinical situation.13 Because of their complete
`bioavailability, intravenous doses are generally
`provided hourly or as a continuous infusion.
`Although intermittent bolus doses of intra(cid:173)
`muscular and subcutaneous opioids are con(cid:173)
`sidered equipotent with IV dose, these modes
`of administration are dosed at longer intervals
`because they provide a slower time course due
`to the systemic absorption required from the
`
`

`

`OPIOID EQUIANALGESIC CALCULATIONS
`
`213
`
`depot site.12 The availability of extended re(cid:173)
`lease oral formulations allow for dosing of mor(cid:173)
`phine as infrequently as every 12-24 hours
`when pain is constant and around-the-clock
`dosing is required. Recently, the use of a sin(cid:173)
`gle dose of an opioid with a long duration of
`action for selected short pain experiences, such
`as migraine headache or postoperative pain,
`has been suggested. 2
`
`HOW TO CALCULATE AN
`EQUIANALGESIC DOSE
`
`There are a number of ways to calculate an
`equianalgesic dose. Choice of method is pri(cid:173)
`marily one of individual preference and style
`of approaching math problems. When properly
`applied, any of the methods described below
`will produce the correct result (Table 2).
`
`RATIOS
`
`One method to use is ratios. For example,
`look at Table 1 and find the oral dose listed for
`morphine (30 mg) and the parenteral dose (10
`mg). This gives a 30:10 or 3:1 ratio for oral to
`parenteral morphine. This means that it takes
`approximately 3 times more morphine orally
`than parenterally to produce the same anal(cid:173)
`gesic effect. One can simply multiply any IV
`morphine amount by 3 to determine the ap(cid:173)
`proximate equianalgesic oral morphine dose.
`Now examine the ratio between oral hydro(cid:173)
`morphone and oral morphine. You can see
`from Table 1 that 7.5 mg of oral hydromor(cid:173)
`phone is equal to 30 mg of oral morphine. 7.5
`mg to 30 mg is a 1:4 ratio (if you can't imme(cid:173)
`diately see this ratio, divide the smaller num(cid:173)
`ber into the larger number, 7.5 goes into 30 four
`times). So a patient taking 4 mg of hydromor(cid:173)
`phone PO q4h is taking the equivalent of 16 mg
`of morphine PO q4h. Setting up a ratio makes
`it easy to view the difference between the 2
`drugs. The difficulty of ratios is that there is not
`always a convenient one, particularly between
`different opioids. Take for example the ratio be(cid:173)
`tween oral hydromorphone (7.5 mg) and the
`parenteral dose of morphine (10 mg). The ratio
`is 7.5:10 or 3:4.
`
`PROPORTIONS
`
`A second method is to set up simple math
`proportions using ratios. Proportions can be set
`up in a number of ways, and still be mathe(cid:173)
`matically correct, as long as the ratios used on
`either side of the equation are kept parallel. For
`example:
`
`Doses from
`Equianalgesic
`Table
`
`Equianalgesic table
`dose of current
`
`Equianalgesic table
`dose of new drug
`
`or
`
`Actual Drug
`Doses
`
`24 hr total dose of
`current drug
`
`24 hr total dose of
`the new drug
`
`Current Drug
`
`New Drug
`
`Equianalgesic table
`dose of current drug
`
`Equianalgesic table
`dose of new drug
`
`24 hr total dose of
`current drug
`
`24 hr total dose of
`the new drug
`
`Both methods of setting up the proportions are
`equally correct. Although an equianalgesic cal(cid:173)
`culation can be performed for a single dose,
`when a change is made it is best to convert the
`total 24-hour amount of opioid currently being
`used to the 24-hour dose of the new preferred
`route and drug, and then divide.this amount by
`the appropriate dosing interval. For example, if
`a patient is receiving a continuous N infusion,
`calculating the oral equivalent of only 1 hour of
`infusion would not be very helpful for deter(cid:173)
`mining an oral dose. Take the following exam(cid:173)
`ple: a patient receiving an N infusion of 7 mg of
`morphine per hour. Using the ratio between oral
`and N morphine from Table 1 (3:1), we can see
`that the equivalent oral dose is approximately (7
`mg X 3 =) 21 mg of morphine. However, read(cid:173)
`ers would agree that we would not want to give
`a patient an oral dose every hour, because the
`duration of action of oral morphine is 3-4 hours
`for shorter acting preparations and 8-24 hours
`for extended release products. It is much easier
`to first add up the total 24-hour amount of N
`
`

`

`214
`
`GORDON ET AL.
`
`TABLE 2. EQUIANALGESIC CALCULATION GUIDE
`
`1 Add up the total amount of current drug given in 24
`hours. Remember to add in both scheduled and
`rescue doses.
`(If two or more different opioids have been taken, they must
`each be converted to the same drug and route)
`
`Example: 1
`Patient is taking I Omg PO morphine q4h. The patient is
`taking 6 doses per day:
`6 doses x 10 mg = 60mg per day
`Convert to oral hydromorphone:
`
`2 Plug numbers into the following proportion:
`Put in 24h dose of
`Go to equianalgesic table -
`current drug
`find dose for current drug
`(from step I)
`N (the 24h dose ofthe
`new drug)
`
`Go to equianalgesic table -
`find dose for new drug
`
`2
`
`30mg PO morphine
`
`60 mg PO morphine
`
`7.5mg PO
`hydromorphone
`
`N (the 24h dose of PO
`hydromorphone)
`
`30mg morphine
`
`Shortcut tip: Look at the left side of the proportion above as a
`fraction. If possible, reduce the fraction. This new fraction
`provides the ratio and applies to the relationship between the
`24h doses, and may immediately show you the value ofN. If
`can see this, skip to step 4.
`3 Solve for N by cross multiplying:
`A
`24h dose of
`Equianalgesic table dose of
`current drug
`30mg morphine
`current drug
`r--=~--~~--~~--~-- = --------~~------~~--~~~--~---
`N
`Equianalgesic table dose of
`7.5mg hydromorphone
`new drug
`
`7.5mg
`hydromorphone
`3
`A
`
`4
`
`60mg morphine
`
`N
`
`60mg morphine
`N
`
`B
`24h dose
`current
`drug
`
`Equianalgesic
`table dose
`X ·
`new drug
`
`Equianalgesic
`table dose
`current drug
`
`B
`60mg
`morphine
`
`XN
`
`7.5mg
`X hydromorphone
`
`30mg
`morphine
`
`XN
`
`c
`24h dose current drug
`
`Equianalgesic table
`dose new drug
`Equianalgesic table dose current drug
`
`X
`
`c
`60mg morphine
`
`=N
`
`X
`
`7.5mg hydromorphone
`
`=N
`
`30mg morphine
`
`D Answer! "N" will be the 24h dose ofthe new drug
`
`D 15mg hydromorphone = N
`
`E Does this answer make sense? Double check. Plug answer
`into the proportion in step A, cross multiply and the numbers
`should be equal.
`4 Look up the duration of action (the dosing interval)
`of the new drug in the equianalgesic table and
`determine how many doses the patient should take
`each day. Divide N by the number of dose per day.
`This gives the amount for each scheduled dose of
`the new opioid.
`
`E 30mg morphine
`
`60mg morphine
`
`=
`
`7.5mg hydromorphone
`
`15mg
`hydromorphone
`4 Hydromorphone can be given every 4h, which is 6
`doses per day. To give 15mg ofhydromorphone in a day,
`divide the 24h dose by 6.
`2.5mg hydromorphone q4h
`Since hydromorphone comes in 2,4, and 8mg tablets, the
`dose would be rounded up or down depending on the
`clinical situation.
`
`This guide illustrates one method of changing from one opioid or route of administration to another. Clinicians
`must be able to identify appropriate opioid doses when a patient requires a change of opioid and/ or route of
`administration. Mastering this skill enables you to determine a dose of a new opioid that is approximately equal
`in analgesic effect to the dose of a former opioid to ensure continued pain relief.
`
`

`

`OPIOID EQUIANALGESIC CALCULATIONS
`
`morphine the patient is currently receiving (7
`mg X 24 hours = 168 mg IV morphine/24
`hours). Again, using the ratio method, multiply
`this total by 3 to determine the approximate
`amount of oral morphine required in 24 hours
`(3 X 168 mg = 504 mg). The new 24-hour total
`can then be divided by the appropriate dosing
`interval based on the duration of action of the
`product being used (eg, for short-acting oral
`morphine divide by 6 dosing intervals, and ad(cid:173)
`minister every 4 hours; for 12-hour formulations
`such as MS-Contin ™ or Oramorph ™ divide by
`2 dosing intervals and administer every 12 hours;
`for 24-hour formulations such as Kadian TM
`(Zeneca Pharmaceuticals, Wilmington, DE) the
`24-hour dose does not need to be divided and
`can be administered as a single dose).
`
`CONTROVERSIES
`
`Recent data from crossover studies have
`questioned the validity of widely published
`equianalgesic tables.22 Among a number of
`equianalgesic doses currently under question,
`are the relative doses of methadone to mor(cid:173)
`phine and hydromorphone, hydromorphone to
`morphine, and oral oxycodone to morphine. In
`addition, the development of novel formula(cid:173)
`tions for new systemic routes of administration
`( eg, transdermal, transmucosal, inhaled) brings
`new challenges to equianalgesic conversions.
`
`METHADONE
`
`Methadone is known for a wide ranging and
`unpredictable plasma half-life (13 to 50 hours),
`and for its progressive duration of analgesia
`with chronic dosing. Whereas the duration of
`analgesia is often only 4 to 8 hours in the first
`few days of therapy, with repetitive dosing, the
`drug is known to accumulate, lengthening dos(cid:173)
`ing interval requirements to only once or twice
`a day.l2
`Some equianalgesic tables propose a dose ra(cid:173)
`tio of 1:1 between oral and parenteral morphine
`and methadone. 13,23 Others, propose a mor(cid:173)
`phine-methadone ratio of 4:1 for the oral route
`and 2.7:1 for the parenteral route? A number
`of authors24-27 have more recently reported
`
`215
`
`major differences in the dose of methadone re(cid:173)
`quired to maintain control of cancer pain when
`compared to previous doses of morphine and
`hydromorphone. In all studies, methadone was
`found to be much more potent than was sug(cid:173)
`gested by single-dose studies.
`Although most equianalgesic tables propose
`a parenteral hydromorphone to oral metha(cid:173)
`done dose ratio ranging from 1:6 to 1:10, data
`from a retrospective study of opioid rotations
`of 65 cancer patients28 whose median total
`equivalent morphine dose before opioid
`change was 1185 mg, found the ratio between
`subcutaneous hydromorphone and oral metha(cid:173)
`done to be 1.14:1. This is approximately 6 to 10
`times higher than previously suggested. Al(cid:173)
`though the dose ratio did not change accord(cid:173)
`ing to the previous opioid dose, it was corre(cid:173)
`lated with the total opioid dose. It is also been
`reported, that contrary to what one might ex(cid:173)
`pect, toxicity from methadone appears to occur
`frequently in patients previously exposed to
`high doses of other opioids than in patients pre(cid:173)
`viously receiving low doses.26 The findings in(cid:173)
`dicate that the ratio between methadone and
`other opioid agonists may vary widely and
`change as a function of the previous dose ex(cid:173)
`posure.26
`
`HYDROMORPHONE
`
`Although short-term studies29 support a
`morphine to hydromorphone equivalency ra(cid:173)
`tio of 7:1 or 5:1, data from more recent long(cid:173)
`term studies30 suggest that the morphine/hy(cid:173)
`dromorphone equivalency ratio changes over
`time and may be more close to 3:1. Data from
`another retrospective study of opioid rotations
`in cancer patients,31 suggest that hydromor(cid:173)
`phone is 5 times more potent than morphine
`when given second, but only 3.7 times more po(cid:173)
`tent when given first. In other words, the opi(cid:173)
`oid to which the patient is rotated is relatively
`more potent.
`
`ORAL OXYCODONE TO MORPHINE
`
`Package inserts for slow release oxycodone
`suggest an equivalency ratio of 2:1 for oral mor-
`
`

`

`2Y6
`
`phine to oral oxycodone. This ratio is derived
`from comparison, double-blind, randomized,
`parallel-group assays of oxycodone to codeine
`and morphine,32,33 and is considered conserv(cid:173)
`ative by some, who instead, recommend a mil(cid:173)
`ligram to milligram conversion for oral mor(cid:173)
`phine to oral oxycodone (1:1). It has also been
`suggested to use a slightly different ratio de(cid:173)
`pending on which direction the switch is being
`made ( eg, from oral morphine to oral oxy(cid:173)
`codone 1.5:1, or 20 mg of oxycodone for every
`30 mg of morphine, and from oral oxycodone
`to oral morphine use 1:1).14 Ratios of 1:1 and
`1.3:1 (oral oxycodone to oral morphine) have
`both been found to be safe and effective in stud(cid:173)
`ies of both chronic advanced cancer pain34 and
`postoperative patients.35
`
`TRANSDERMAL FENTANYL
`
`If not the most controversial, perhaps the
`most challenging opioid formulation for which
`to calculate an equianalgesic dose is transder(cid:173)
`mal fentanyl. Fentanyl is generally considered
`50-150 times more potent than morphine and
`is well known for its use in anesthesia.36 Trans(cid:173)
`dermal fentanyl patches capitalize on the
`drug's lipid solubility and contain a rate-con(cid:173)
`trolling membrane that allows for continuous
`72-hour systemic drug delivery through per(cid:173)
`cutaneous absorption.37 As mentioned previ(cid:173)
`ously, equianalgesic tables traditionally com(cid:173)
`pare only per os and parenteral doses.
`However, as interest and use in newer formu(cid:173)
`lations such as transdermal fentanyl grow,
`there is a demand for equianalgesic doses of
`novel routes such as transdermal, transmu(cid:173)
`cosal, and inhalation.
`Although the pharmacokinetics of transder(cid:173)
`mal fentanyl are fairly well defined, the rec(cid:173)
`ommended range of equianalgesic doses is con(cid:173)
`siderably variable. Package inserts lists the
`recommended conversion for 25 p,g/hr of
`transdermal fentanyl at 45-134 mg of oral mor(cid:173)
`phine per day.38 Many clinicians use a 2:1 ra(cid:173)
`tio between oral morphine and transdermal
`fentanyl. By dividing the current 24-hour total
`dose of oral morphine by two, one can easily
`determine the approximate microgram starting
`dose of transdermal fentanyl. For example, a
`
`GORDON ET AL.
`
`patient taking 400 mg of oral morphine in 24
`hours would be switched to 200 p,g/hr patch
`of transdermal fentanyl Q72 hours. Clinical
`studies continue to report that either method
`(package insert or ratio) is conservative, with
`up to 50% of patients requiring upward dose
`titration after initial application.39-4°
`
`CONCLUSIONS
`
`From their earliest use,41 equianalgesic tables
`have been recognized for several weaknesses.
`Many of the relative potencies listed on equian(cid:173)
`algesic tables are derived from single-dose or
`short-term studies with limited control on sub(cid:173)
`ject differences such as psychological charac(cid:173)
`teristics, previous degree of opioid exposure,
`nature and severity of pain, random fluctua(cid:173)
`tions in pain severity, age, and sex. The pio(cid:173)
`neering studies by Houde and colleagues42
`from which most equianalgesic values are de(cid:173)
`rived, were developed to address the pharma(cid:173)
`ceutical industry's needs to know the dose to
`use when introducing new analgesics into
`practice,2° not for clinicians to determine treat(cid:173)
`ment decisions. In a recent editorial, Foley and
`Houde20 discuss the increasing confusion and
`misinterpretation of equianalgesic dose tables
`as data from opioid rotation studies is added.
`They caution, that if such tables are to be used
`clinically, we must carefully define how the ra(cid:173)
`tios are established, and the confidence limits
`for each study utilized. In addition, although
`pharmacokinetic factors and pharmacodynam(cid:173)
`ics studies can be used to help predict equianal(cid:173)
`gesia, psychological factors will also· influence
`the analgesic effectiveness of an opioid 12 and
`should be considered in treatment decisions.
`Providing quality pain management contin(cid:173)
`ues to be a major healthcare challenge. As sci(cid:173)
`ence and collective clinical experience con(cid:173)
`verge, more information is available to help
`guide clinicians in decisions about analgesic
`therapy. Equianalgesic calculation is a quintes(cid:173)
`sential skill for all clinicians, who for many rea(cid:173)
`sons, may need to switch opioid agents or
`routes for patients in pain. The process of
`switching from one opioid to another is com(cid:173)
`plex and much more than performing a simple
`mathematical calculation based on an equianal-
`
`

`

`OPIOID EQUIANALGESIC CALCULATIONS
`
`gesic conversion table. Exact conversion factors
`and procedures for switching are still un(cid:173)
`known.
`Many of the commonly accepted equianal(cid:173)
`gesic ratios are coming under question and re(cid:173)
`examination. It is unlikely we will ever know
`with precision, an exact formula to predict a
`certain outcome. As in all aspects of pain man(cid:173)
`agement, individual characteristics and re(cid:173)
`sponse must be carefully considered and as(cid:173)
`sessed. Even with experienced clinicians, use of
`recommended ratios may result in undertreat(cid:173)
`ment or the reverse, side effects and toxicity.
`More information and carefully controlled
`studies are needed.
`
`ACKNOWLEDGMENTS
`
`We wish to thank and acknowledge June
`Dahl, Ph.D. and David Weissman, M.D. for
`their guidance and leadership in teaching
`equianalgesic calculation in the Cancer Role
`Model Program,