VOLUME 32 䡠 NUMBER 16 䡠 JUNE 1 2014

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Principles of Opioid Use in Cancer Pain

Russell K. Portenoy and Ebtesam Ahmed
All authors: Beth Israel Medical Center,
New York, NY. A B S T R A C T

Published online ahead of print at The management of pain is an essential aspect of comprehensive cancer care. Positive
www.jco.org on May 5, 2014.
outcomes can be achieved in most patients with widely available therapies. There is a broad
Authors’ disclosures of potential con- consensus that opioid-based pharmacotherapy is the first-line strategy for the treatment of
flicts of interest and author contribu-
moderate or severe chronic pain in populations with active disease, and treatment guidelines
tions are found at the end of this
article.
have been developed from the known pharmacology of these drugs, extant data, and
extensive clinical experience. This article describes the major opioid analgesics available for
Corresponding author: Russell K.
the treatment of cancer-related pain and reviews the key elements for safe and effective
Portenoy, MD, Department of Pain
Medicine and Palliative Care, Beth
prescribing, including selection of the best drug and route, approaches to titration and
Israel Medical Center, First Avenue at long-term administration of baseline and supplemental doses, rotation from one drug to
16th St, New York, NY 10003; e-mail: another in poorly responsive patients, and management of opioid risks.
rporteno@chpnet.org.

© 2014 by American Society of Clinical J Clin Oncol 32:1662-1670. © 2014 by American Society of Clinical Oncology
Oncology

0732-183X/14/3216w-1662w/$20.00
INTRODUCTION OPIOID PHARMACOLOGY
DOI: 10.1200/JCO.2013.52.5188

The prevalence of chronic pain in populations
with solid tumors is 15% to 75%, depending on
the extent of disease, type of cancer, treatment
setting, and other factors.1 When the etiology of
pain is related to active cancer of any type, and its
intensity is moderate or severe, there is consensus
that opioid therapy is first-line therapy.2,3 Despite
limited high-quality evidence,4 this consensus has
evolved as an international standard of care that
has endured since it was codified by the WHO
more than a quarter century ago.5 Unfortunately,
neither this consensus nor the publication of
evidence-based guidelines2 has corrected the
problem of undertreatment, which continues to
be driven by the need for professional education
about best practices6,7 and limited access to opi-
oid drugs in many parts of the world.
The use of opioid therapy requires a com-
prehensive assessment that characterizes the
pain and provides the information necessary
for a plan that targets pain while addressing
other problems4 (Table 1). Pain assessment al-
lows treatment that is individualized and balances
the benefits and burdens of various therapies in
relation to the broader goals of care.3,8 The ap-
proach to analgesia may involve consideration of
disease-modifying therapy or any of a variety of
specific therapies (Table 2). Unrelieved moderate
or severe pain suggests that a trial of opioid ther-
apy or an adjustment in the current opioid regi-
men is needed.
Opioids act by binding to receptors in three families:
mu, kappa, and delta. The mu receptor family has
numerous subtypes related to splice variants and
alleles of the opioid receptor mu-1 (OPRM-1) gene.
This genetic variation helps explain the large intra-
individual and interindividual variation in the re-
sponse to the different mu agonist opioids.9
Most opioid drugs are mu agonists, which may
be divided into the pure agonists and the agonist-
antagonists; the latter category includes mixed
agonist-antagonist drugs and partial agonist drugs
(Table 3). Although cancer pain management has
historically relied on the long-term use of the pure
mu agonist drugs (Table 4), both the partial agonist
buprenorphine and centrally acting drugs with
mixed mechanisms, specifically tramadol and tap-
entadol, are sometimes used.
Pure Mu Agonists
With the exception of meperidine, which has
an active metabolite that increases the risk of
long-term therapy, any of the pure mu agonist
opioids may be used to treat cancer pain. Patients
who are opioid naive or have limited opioid
exposure are usually managed initially with a
short-acting drug, either an immediate-release,
single-entity formulation, such as morphine or
hydromorphone, or a combination product con-
taining a nonopioid (usually acetaminophen)
plus an opioid such as oxycodone or hydro-
codone. Drugs from other classes, typically one of
the mixed-mechanism drugs, also may be used,

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 Principles of Opioid Use in Cancer Pain

Table 1. Key Objectives of the Pain Assessment in Populations With Table 2. Categories of Treatments for Pain Related to Cancer
Active Cancer
Category Type of Treatment
1. To characterize the multiple dimensions of the pain
Pharmacologic Opioid analgesics
Intensity
Nonopioid analgesics
Temporal features: onset, course, daily fluctuation, and breakthrough pains
Nontraditional analgesics (adjuvant analgesics)
Location and radiation
Interventional Injection therapies
Quality
Neural blockade
Provocative or relieving factors
Implant therapies
2. To formulate an understanding of the nature of the pain
Rehabilitative Modalities such as heat and cold
Etiology
Therapeutic exercise
Inferred pathophysiology
Occupational therapy
Pain syndrome
Hydrotherapy
3. To characterize the impact of the pain on quality-of-life domains
Therapies for specific disorders (eg,
Effect on physical functioning and well-being lymphedema)
Effect on mood, coping, and related aspects of psychological well-being Psychological Psychoeducational interventions
Effect on role functioning and social and familial relationships Cognitive-behavioral therapy
Effect on sleep, mood, vitality, sexual function Relaxation therapy, guided imagery, other
4. To clarify the extent of neoplastic disease, planned treatment, and types of stress management
prognosis Other forms of psychotherapy
5. To clarify the nature and quality of prior pain evaluation and treatments Neurostimulation Transcutaneous
6. To elucidate medical comorbidities Transcranial
7. To elucidate psychiatric comorbidities Percutaneous peripheral nerve and spinal
Substance use history cord/root stimulation
Depression and anxiety disorders Integrative (complementary Acupuncture
Personality disorders or alternative) Massage
8. To determine need for other palliative care interventions Movement therapies
Other symptoms Others
Distress related to psychosocial or spiritual concerns
Caregiver burden and concrete needs
Problems in communication, care coordination, and goals setting

Hydromorphone, oxymorphone, and oxycodone, like mor-

and some patients appear to benefit when a long-acting pure mu
agonist drug, such as modified-release morphine or transdermal
fentanyl, is used to initiate treatment.2
The historical preference for codeine to initiate opioid therapy is
waning, with new information about the risks associated with
genomic variation in its metabolism.10 Codeine is a prodrug and
requires conversion to morphine via the CYP2D6 isoenzyme of the
P450 hepatic enzyme system. CYP2D6 is highly polymorphic, with
more than 90 known allelic variants. Five percent to 10% of patients
inherit a slow metabolizer phenotype and may experience limited or
no therapeutic benefit from codeine. Patients who are ultrarapid me-
tabolizers may develop a higher-than-expected morphine level, result-
ing in a potential overdose.
Morphine is the prototypic opioid drug for severe cancer pain.
There is no evidence, however, that morphine offers superior safety or
efficacy when compared with any other pure mu agonist drug, and
there is no way to predict whether a patient will have a more favorable
balance between analgesia and adverse effects with morphine or an-
other opioid. Morphine is metabolized by the liver into two active
metabolites, morphine-6-glucuronide (M6G) and morphine-3-
glucuronide (M3G). M6G binds to the mu receptor and contributes to
opioid effects during therapy; M3G is not an opioid and may cause
toxicity, such as myoclonus and agitation.11 These metabolites are
cleared by the kidneys, and in patients with kidney disease, metabolite
concentration may be high. If renal function is declining or fluctuat-
ing, use of an opioid without active metabolites, such as fentanyl, or
one with lower concentration of renally cleared metabolites, such as
hydromorphone, is preferable.12
phine, are available in both immediate-release and modified-release
oral formulations. Oxycodone binds to both mu and kappa receptors,
but the clinical implications of this dual binding are uncertain. In
some countries, such as the United States, oxycodone has become the
largest contributor to a rising problem of prescription drug abuse.
Although drug abuse is not prevalent among those with cancer pain, it
has highlighted the need for appropriate risk management in all pop-
ulations and has led to the development of an abuse-deterrent formu-
lation that cannot easily be crushed or converted to an injectable.
Other modified-release formulations are being developed or reformu-
lated with similar technology.
Fentanyl is a highly lipophilic opioid and is used for cancer pain
in transdermal and transmucosal immediate-release formulations.
The patch is indicated for chronic pain and the transmucosal formu-
lations are indicated for cancer-related breakthrough pain. Clinical
experience and limited data suggest that the transdermal formulation
is preferred by some patients when pill burden is high, when a dosing
frequency of 2 to 3 days would be beneficial, or when GI symptoms are
prominent.13,14 Comparative data from randomized trials are limited,
however, and the superiority of this formulation has not been con-
firmed.15 The lowest dose patch is 12 ␮g/h and can be used in opioid-
naive patients; titration can ensue by using larger doses and multiple
patches. Specific risks of this formulation include increased drug ab-
sorption when the patch is exposed to heat, either with fever or an
external heating pad, and the possibility of local burns if the patch is
worn during magnetic resonance imaging. It is prudent to remove the
patch before the scan begins and replace it after.
Recent guidelines call for the use of methadone only by clinicians
who have acquired the skills for safe use of this opioid.2 This drug has

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 Portenoy and Ahmed

Table 3. Classification of Opioid Drugs

Drug Type and Name Comment
Pure agonists
Codeine No clinically relevant ceiling effect to analgesia; as dose is raised, analgesia is achieved or dose-limiting side
Morphine effects supervene
Fentanyl Most commonly used for moderate to severe pain
Hydrocodone
Hydromorphone
Levorphanol
Meperidine
Methadone
Oxycodone
Oxymorphone
Agonist-antagonist
Mixed agonist-antagonists Ceiling effect for analgesia
Butorphanol
Pentazocine Some produce psychotomimetic side effects more readily than do pure agonist
Nalbuphine Potential to induce acute abstinence in patients with physical dependence to agonist opioids
Partial agonists
Buprenorphine Transdermal buprenorphine is available in a lower dose formulation in the United States and a higher dose
formulation in other countries and is used for cancer pain
Centrally acting drugs with opioid effects
Tramadol Analgesic mechanism is partially mu opioid and partially related to serotonergic and/or noradrenergic effects
Tapentadol Ceiling effect imposed by safe dosing; typically considered as an option for initial therapy in patients with
no prior opioid exposure
Pure antagonists
Methylnaltrexone Administered for prevention or reversal of opioid effects
Naloxone
Naltrexone
Alvimopan

been favored by some because of its low cost, potential for high
efficacy, and perceived value in reducing the risk of abuse in patients
predisposed to addiction. Unfortunately, increased use has become
associated with a high rate of serious adverse events, particularly in
populations with noncancer pain. Safe administration of methadone
requires knowledge of its unique characteristics.
Methadone pharmacokinetics are highly variable. The half-life
averages about 24 hours but ranges from less than 15 hours to more
than 130 hours.16 Although the time to approach steady-state after
initiating or increasing the dose is 5 to 7 days in most patients, it can
extend to a few weeks in some. Plasma concentration slowly increases
until steady-state is approached, and monitoring after each dose ad-
justment must be continued long enough to ensure that the patient
has stabilized on the higher dose.
Methadone potency can be much higher than anticipated in
patients already receiving a pure mu opioid agonist. This unantici-
pated potency presumably is related to the D-isomer in the commer-
cially available racemate, which blocks the N-methyl-D-aspartate
receptor and may have analgesic effects and reverse opioid tolerance.
As a result of this potential for high potency, a switch to methadone
from another mu agonist drug requires a substantial reduction in
the calculated equianalgesic dose.17 Methadone also can prolong the
heart-rate corrected QT (QTc) interval,18 and in most cases, a pre-
treatment review of the electrocardiogram is needed to determine
whether there is a relative contraindication (QTc interval from 450 to
500 ms) or a strong contraindication (QTc interval ⬎ 500 ms) to
treatment. Should therapy proceed, the electrocardiogram should be
reassessed, at minimum, early during dose titration and when the dose
exceeds 100 mg per day. Finally, methadone is a weak serotonin
reuptake inhibitor and has a complex metabolism that involves both
CYP3A4 and CYP2D6. As a result, drug-drug interactions are rela-
tively likely,19 and dosing strategies to limit risk are particularly impor-
tant when the patient is receiving other drugs.
Partial Agonists
Buprenorphine, a partial mu agonist with a high affinity for the
mu receptor, is available in some countries in sublingual formulations
indicated for the treatment of opioid addiction and transdermal for-
mulations indicated for chronic pain. Although experience with bu-
prenorphine in the management of cancer pain is limited,15 there is
accumulating evidence that the transdermal formulation may be
useful.20-22 The combination of convenient dosing (a 7-day patch)
and some favorable pharmacologic characteristics, such as efficacy in
the treatment of opioid addiction, a ceiling effect for respiratory de-
pression, and lesser effects on neuroendocrine function than pure mu
agonists, may support greater use in the cancer population.23
In the United States, the transdermal formulation is available in
doses of 5 ␮g/h, 10 ␮g/h, and 20 ␮g/h; higher doses, are available in
other countries. As a partial agonist, administration of buprenorphine
to opioid-treated patients has the potential for inducing withdrawal if
physical dependence is present; it is therefore prudent to limit treat-
ment to those who are opioid naive or are receiving a low-dose opioid
regimen. Because of the high affinity of buprenorphine for the mu
receptor, serious toxicity, should it occur, requires high and prolonged

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 Principles of Opioid Use in Cancer Pain

Table 4. Pure Mu Agonist Opioid Drugs Commonly Used in the Management of Cancer Pain
Equianalgesic Dose

Amount Method of Half-Life Duration

Drug (mg) Administration (hours) (hours) Comments
Codeine 200 PO 2-4 4-6 Sometimes used for moderate pain but not preferred because of
unpredictability introduced by genetic differences in conversion of
prodrug (codeine) to active metabolite (morphine)
Hydrocodone 30 PO 3-4 4-8 Used for moderate pain in a combination product containing a nonopioid
Morphine 10 IM/IV/SC 2-3 3-4 Standard for comparison for opioids; multiple routes available
30 PO 2-3 3-6
Modified-release morphine 30 PO 2-3 8-12
Sustained- release morphine 30 PO 2-3 12-24
Hydromorphone 1.5 IM/IV/SC 2-3 3-4 Potency and high solubility may be beneficial for patients requiring high
7.5 PO 2-3 3-6 opioid doses and for subcutaneous administration
Modified-release 7.5 PO 2-3 24
hydromorphone
Oxycodone 20 PO 2-3 3-6 Available as a single entity or combined with aspirin or acetaminophen
Modified-release oxycodone 20 PO N/A 8-12
Oxymorphone 1 IM/IV/SC — 3-6
10 PR — 4-6
15 PO
Modified-release 15 PO N/A 12
oxymorphone
Levorphanol 2 IM/IV/SC 12-15 3-6 With long half-life, accumulation possible after beginning or increasing
4 PO 12-15 3-6 dose
Methadone 10 IM/IV/SC ⬍ 75-⬎ 130 6-8 May be far more potent than indicated in the table, presumably because
20 PO potency of available racemate is due in part to the D-isomer, an
NMDA antagonist that may reverse tolerance and augment analgesia;
with highly variable half-life, patients require greater vigilance for
weeks, until steady state has definitely occurred; also can prolong the
QTc interval, and in most cases, baseline ECG, and repeat ECGs
during dose titration, should be checked
Fentanyl 50-100 ␮g IV/SC 7-12 1-2 Can be administered as a continuous IV or SC infusion
Fentanyl transdermal system — N/A 48-72 per Refer to package insert for oral and parenteral medication equianalgesic
patch dosing guidelines. Not usually recommended for opioid-naive patients
in currently available doses. Not recommended for acute pain
Transmucosal fentanyl citrate — 7-12 1-2 New formulations indicated for the treatment of breakthrough pain.
formulations Varied products, including intraoral, buccal tablet, buccal patch,
sublingual, and intranasal formulations. Not recommended for opioid-
naive patients. Initial dose should always be one of the lowest doses
available, even if the patient is receiving a relatively high dose of a
scheduled opioid

Abbreviations: ECG, electrocardiogram; IM, intramuscular; IV, intravenous; N/A, not applicable; NMDA, N-methyl-D-aspartate; PO, orally; PR, per rectum; SC,
subcutaneous.

antagonist doses (usually naloxone) to achieve reversal. Buprenor-
phine can also prolong the QTc interval, but this effect is less than that
produced by methadone.24
Mixed-Mechanism Drugs
Tramadol and tapentadol are centrally acting analgesics whose
mechanism of action depends on both mu agonism and monoamine
(serotonin and norepinephrine) reuptake inhibition. There is no evi-
dence that tramadol is superior to pure mu agonists for cancer
pain,25,26 but nonetheless, it is widely used in some countries, partic-
ularly in patients who are opioid naive or have limited opioid expo-
sure. Tapentadol is a relatively new drug, and there is little published
experience in cancer pain.27 Both of these drugs have a ceiling dose
imposed by the risks associated with the monoaminergic mechanism.
PRINCIPLES OF PRESCRIBING
Guidelines for optimizing the outcome of opioid therapy in popula-
tions with active cancer derive from the known pharmacology of these
agents, extensive clinical experience, and a slowly expanding evi-
dence base.2,3,8,28
Selection of Drug and Route
Opioid therapy usually is initiated in opioid-naive patients who
are able to use oral medications. As noted, conventional treatment
usually relies on a short-acting, single-entity opioid or combination
product. There is no evidence for drug-selective effects that would
uniformly justify the selection of one drug over another, and the drug
chosen is typically based on the experience of the clinician, availability,
cost, and prior patient experience. The starting opioid dose usually is
roughly equivalent to 5 to 15 mg of oral morphine every 3 to 4 hours.
Initial as-needed dosing allows rapid titration of the dose through
frequent administration or, if necessary, rapid dose escalation by in-
crements of 33% to 50%.
If pain persists and multiple daily doses are required, it is com-
mon to transition the patient to a single-entity, long-acting opioid
formulation (Table 4). This change can reduce pill burden, potentially
enhance adherence, and may facilitate dose titration by distinguishing

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 Portenoy and Ahmed
between baseline pain and breakthrough pain. It simplifies the admin-
istration of a fixed scheduled (around-the-clock) regimen, which may
have the ability to prevent pain from occurring.29
Although the choice of opioid usually is determined by expe-
rience, access, and cost, it may be reasonable to consider either
transdermal buprenorphine or methadone in those with a signifi-
cant history of alcohol or drug abuse. The impact of doing so on
adherence and other outcomes has not been evaluated in cancer
populations, but the efficacy of these two drugs in the treatment of
opioid addiction offers at least theoretical reasons to offer one or
the other to these patients.
Given the variation among patients, other strategies for drug
selection are worthy of mention. Some patients do not prefer a switch
to a long-acting formulation. If the ability to exercise finer control over
dosing is valued by the patient, continuing treatment by using a
short-acting, single entity drug such as oral morphine should be con-
sidered. Other patients who experience pain that is likely to persist and
increase over time can be considered for initial treatment with a
long-acting, modified-release formulation.2 The challenge inherent in
rapidly titrating the dose of a drug that is administered once or twice
daily can be overcome by concurrent prescription of a short-acting
drug for breakthrough pain.
Conventionally, the oral and transdermal routes are used for
chronic pain, and alternative routes are considered for specific rea-
sons. The intramuscular route is not recommended because it is pain-
ful and provides no pharmacologic advantage, and the rectal route
usually is considered only when the oral route is unavailable and
treatment duration will be limited. There is anecdotal experience with
longer-term rectal treatment by using a modified-release oral formu-
lation.30 The potency of rectally administered opioids is believed to
approximate oral dosing, but absorption is variable, and the relative
potency between oral and rectal doses may be higher or lower than
expected. Accordingly, a switch from oral to rectal dosing is usually
accompanied by a reduction in the equivalent dose.
Intravenous and subcutaneous infusions are often used, particu-
larly in the management of pain or dehydration in advanced illness.
Patient-controlled analgesia can be accomplished with either. Contin-
uous subcutaneous infusion usually involves insertion of a butterfly
catheter under the skin of the chest wall or abdomen for a week or
more; any injectable drug or drug combination can be delivered in this
way.31 Methadone is not preferred, however, because of the potential
for local skin reactions at the needle site. Hyaluronidase can be added
to the infusate to permit high-volume subcutaneous infusion for
hydration or to facilitate the delivery of relatively high drug doses.32-34
Long-term intravenous therapy may be accomplished by using a pe-
ripherally inserted central catheter or an implanted central venous
access device.
Dose Individualization
The success of opioid therapy requires individualization of the
dose by using a process of dose titration, by which safe increments in
dose are undertaken to identify a stable dose associated with a favor-
able balance between analgesia and adverse effects. Titration is typi-
cally needed at the start of therapy and periodically thereafter.
Conventionally, a dose increment is calculated as either 33% to 50% of
the average total daily dose during the prior few days or a daily amount
equal to the average of the supplemental doses taken by the patient
each day during the prior few days.
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There is no ceiling dose for the pure mu agonist opioids, and the
dose may be increased until acceptable analgesia is produced or intol-
erable and unmanageable adverse effects supervene. Most patients will
never require a daily dose higher than the equivalent of 300 mg of oral
morphine per day. It is therefore prudent to view the need for a dose
above this level as a signal to carefully reassess the causes of the pain
and the possibility that other factors, such as comorbid psychiatric
disease or other sources of distress, are driving pain reports. This
assessment may suggest that other types of interventions are needed.
If a favorable balance between analgesia and adverse effects is
obtained, this is usually maintained for a prolonged time. If dose
escalation produces intolerable and unmanageable adverse effects,
however, the patient should be considered to be poorly responsive to
the current regimen. This outcome necessitates reassessment and a
change in the analgesic strategy. Common approaches include more
aggressive adverse effect management, the addition of one or more of
the adjuvant analgesics, and so-called opioid rotation.35
Opioid Rotation
The change from one opioid to which a patient is poorly respon-
sive to another is usually accompanied by a better therapeutic
outcome.36 The reasons for this phenomenon are unknown but pre-
sumably relate to incomplete cross-tolerance between opioids that
occurs at the multiple mu receptor subtypes possessed by each indi-
vidual. A recent survey observed that 31% of ambulatory patients with
cancer pain underwent rotation, yielding benefit in more than
two thirds.36
To switch from one opioid to another, the information contained
on a standard equianalgesic dose table must be consulted (Table 4).
This information originates from a large number of relative potency
studies that were well controlled but not representative of the usual
situation encountered in practice.37 The patients in these studies typ-
ically had little prior opioid exposure and evaluated outcomes after
single doses. These populations were not racially and ethnically di-
verse, and there are few data specific to the elderly or to children. Given
these differences between the study populations and patients, the
ratios in these tables must be adapted to ensure the safety of opioid
rotation. Consensus-based guidelines for opioid rotation incorporate
standard reductions in the equianalgesic doses and clinical judgment
(Table 5).38
Management of Breakthrough Pain
Breakthrough pain is a transitory severe acute pain that occurs on
a background of chronic pain that is controlled by an opioid regimen.
The phenomenon is highly prevalent and associated with adverse
pain-related outcomes.39-41 The use of supplemental doses offered as
needed in combination with a fixed scheduled opioid regimen, an
approach known as rescue dosing, has become a widely accepted
strategy to manage breakthrough pain.
Guidelines for the treatment of breakthrough pain have been
developed on the basis of expert opinion.42,43 Assessment of the break-
through pain itself is a key guideline and may suggest the value of a
primary therapy, such as radiation to bone metastases.
Rescue dosing is generally considered to be appropriate for
most patients with chronic cancer pain who are receiving opioid
therapy with a long-acting drug. The rescue dose may be a
single-entity oral opioid formulation, such as immediate-
release hydromorphone, morphine, oxycodone, oxymorphone,
JOURNAL OF CLINICAL ONCOLOGY
 Principles of Opioid Use in Cancer Pain

Table 5. Guidelines for Opioid Rotation38

Step 1
Select the new drug on the basis of prior experience, availability, cost, and other factors.
Calculate the equianalgesic dose from the equianalgesic dose table.
If switching to any opioid other than methadone or fentanyl, identify an automatic dose reduction window of 25%–50% less than the calculated
equianalgesic dose.
If switching to methadone, the automatic dose reduction window is 75%–90%, rarely converting to methadone at a dose higher than 40 mg per day.
If switching to transdermal fentanyl, do not do an automatic dose reduction; use the calculated equianalgesic dose included in the package insert.
Select a dose closer to the lower bound (25% reduction) or the upper bound (50% reduction) of the automatic dose reduction window on the basis of a
judgment that the equianalgesic dose table is relatively more or less applicable to the characteristics of the regimen or patient.
Select a dose closer to the upper bound if the patient is receiving a relatively high dose of the current opioid, is not white, or is elderly or medically frail.
Select a dose closer to the lower bound otherwise and particularly if being switched to a different route using the same drug.
Step 2
On the basis of assessment of pain severity and other medical or psychosocial characteristics, increase or decrease the calculated dose by 15%–30% to
enhance the likelihood that the initial dose will be effective, or conversely, unlikely to cause withdrawal or adverse effects.
Assess response and titrate the dose of the new opioid regimen to optimize outcomes.
If a supplemental dose as needed is used, calculate this at 5%-15% of the total daily opioid dose and administer at an appropriate interval; transmucosal
fentanyl formulations are exceptions and always should be initiated at one of the lower doses.

or a transmucosal immediate-release fentanyl formulation. Res-
cue dosing during long-term parenteral infusion typically is
provided via a patient-controlled analgesia system.
The transmucosal immediate-release fentanyl formulations are
indicated for cancer-related breakthrough pain. In the United States,
six formulations have been approved, including a lozenge, a sublin-
gual tablet, a nasal spray, an effervescent buccal tablet, a buccal film,
and sublingual spray. All of these products are required by the US
Food and Drug Administration to participate in a risk evaluation and
mitigation strategy (REMS), the purpose of which is to reduce the risk
of unintentional overdose and abuse. The REMS mandates an online
education program for prescribers and registration of the patient,
physician, and the dispensing pharmacist.
Studies of the transmucosal immediate-release fentanyl formu-
lations have demonstrated efficacy in cancer-related breakthrough
pain, with onset of effect that is faster than that expected with oral
opioid formulations.44 These studies have generally failed to find dose
proportionality between the effective dose of the transmucosal prod-
uct and the dose of the baseline opioid regimen, which suggests that
treatment with a transmucosal fentanyl formulation should be initi-
ated at one of the lower available doses, irrespective of the baseline
dose.44 In contrast, rescue dosing with oral drugs has conventionally
assumed dose proportionality, with the rescue dose 5% to 15% of the
daily dose.
Few studies have compared the transmucosal immediate-release
fentanyl formulations with other drugs, but those extant suggest that
they may be more efficacious than oral morphine for breakthrough
pain.45 Given the cost of these newer formulations, however, and
concern about unintentional overdose, their positioning relative to
oral drugs remains ill-defined. It is reasonable to consider one of these
drugs in those patients who have not experienced benefit from an oral
rescue dose as a result of a mismatch in the timing of the pain and the
onset of drug effect, and perhaps in those patients who are unlikely to
benefit from an oral drug because of the rapidity with which break-
through pain appears and worsens.
Management of Adverse Effects
Adverse effect management should be considered a necessary
element in the clinical approach to opioid therapy. The most common
treatment-limiting adverse effects are constipation and mental cloud-
ing or somnolence. Constipation is highly prevalent and presumably
multifactorial in most patients.46 Prophylactic treatment is indicated
in those with predisposing factors. Management may involve an in-
crease in dietary fiber and hydration if appropriate and a simple oral
regimen by using a surfactant, such as docusate, and either an osmotic
agent (eg, a poorly absorbed sugar such as sorbitol or lactulose, or
polyethylene glycol) or a stimulant cathartic (eg, bisacodyl or senna).
In some countries, including the United States, new drug therapies
approved for opioid-induced constipation include peripherally acting
opioid antagonists, such as methylnalthrexone, and lubiprostone. The
evidence for the efficacy of opioid antagonists for this indication
is strong.47,48
The mental clouding and somnolence caused by opioids often
wanes over a period of days to weeks but can be persistent, especially if
other factors augment the effect. Limited supporting data suggest
benefit from the coadministration of a psychostimulant, such as
methylphenidate or modafinil, for patients with persistent symp-
toms.49 Other opioid-related adverse effects that are less common but
well recognized include nausea or pyrosis, dry mouth, urinary reten-
tion, itch, and myoclonus. Treatment strategies for these problems
are empirical.8
Opioids also are associated with risks that may be occult for some
time, ultimately presenting when severe enough to pose substantial
concern. For example, opioid use may worsen sleep apnea of any type
or cause a syndrome of opioid-induced sleep-disordered breathing.50
Evaluation should be considered when the clinical scenario suggests
that interventions may be appropriate for addressing disturbed sleep
or the risks associated with sleep apnea.
Neuroendocrine effects represent a similar situation. Opioid-
induced hypogonadism is a common problem and raises concern
about the potential for sexual dysfunction, accelerated bone loss,
mood disturbance, and fatigue.51 Currently, there is no evidence to
guide treatment in the cancer population, but carefully selected pa-
tients may be considered for hormonal therapy if the long-term ben-
efits are likely to exceed the risks.
Opioid-induced hyperalgesia also may be considered an adverse
effect of opioid therapy. This phenomenon has been clearly demon-
strated in animal models and may explain the anecdotal occurrence of

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 Portenoy and Ahmed

escalating pain in the absence of worsening pathology during opioid
therapy.52,53 Clinical observations suggest that opioid-induced hyper-
algesia is rarely the driver of clinical pain, particularly when pain is
related to a progressive illness, but the possibility should be considered
whenever pain is escalating in the absence of worsening pathology,
and particularly when tremulousness, confusion, or skin sensitivity
occur simultaneously. If suspected, it is reasonable to rotate the opioid
or encourage the use of nonopioid strategy for pain control.
Risk Management
Nonadherence, drug abuse, addiction, unintentional overdose,
and diversion of drugs into the illicit marketplace are known risks of
opioids and other controlled prescription drugs.54 To manage opioid
therapy safely, clinicians must have a working knowledge of these
problems. The increase in prescription drug abuse that has occurred in
the United States during the past decade underscores the need for
basic skills in risk assessment and management and has led the US
Food and Drug Administration to implement a voluntary REMS
program for extended-release opioids.55,56
Risk management requires an understanding of key phenom-
ena.57 Addiction is a disease with a strong genetic basis characterized
by loss of control, craving, compulsive use, and continued use despite
demonstrable harm from the drug. Addiction may or may not be
accompanied by physical dependence, which is defined solely by the
potential for an abstinence syndrome after abrupt dose reduction or
the administration of an antagonist, or by tolerance, which is defined
by a decline in drug effect over time. Addiction is also different from
drug abuse, which refers to the use of any drug outside of social norms.
In the medical setting, abuse behaviors also may be characterized by
other descriptors, such as aberrant drug-related behavior or nonad-
herence behavior.58 Finally, diversion is a legal concept, referring to
the distribution of a drug into the illicit marketplace.
All prescribing of opioids to ambulatory patients should be in-
formed by a universal precautions strategy (Table 6).8,58 Physicians are
required to stop prescribing when there is a strong likelihood that
diversion of prescribed drugs is occurring, but other problematic
behaviors can be managed as medical issues, based on the evaluation
of current risk and benefit. Appropriate consultation with a specialist
in addiction medicine, pain medicine, or palliative care is reasonable
when drug-related behavioral problems are complex.
In conclusion, the consensus that opioid-based pharmacother-
apy is the mainstay approach for the long-term treatment of chronic

Table 6. Principles of Risk Management During Opioid Therapy for Pain

Principle Goals Strategies Comment
Stratify risk To clarify the likelihood of future Consider higher risk if: All patients should undergo risk assessment
aberrant drug-related behavior ● History of alcohol or drug abuse and stratification
● Family history of alcohol or drug abuse Although many questionnaires have been
● Major psychiatric disorder developed to predict aberrant behavior or
Other factors that suggest risk: addiction, the clinical assessment is
● Cancer associated with heavy alcohol use or generally used in practice
smoking
● Current heavy smoking
● Younger age
● History of automobile accidents, chronic
unemployment, limited support system
Factors that may mitigate risk:
● Poor performance status
● Limited prognosis
● Active recovery program
Structure therapy Practices to match monitoring Strategies include The decision to implement one or more of
commensurate with risk and, when needed, ● Use of urine drug screening these strategies is a matter of clinical
with risk help patients maintain control ● Small amounts prescribed judgment
● No use of short-acting drugs
● Use of one pharmacy
● Pill counts at time of visit
● Required consultations
Assess drug-related Track drug use in tandem with Monitor Broad monitoring of outcomes is consistent
behaviors over all relevant outcomes ● Drug-related behavior (eg, need for early refills, with integration of pain management into
time obtaining multiple prescriptions) a palliative care model
● Pain relief
● Adverse drug effects
● Effect of drug on other outcomes
Respond to Clinician compliance with laws If the patient engages in aberrant drug-related behavior: Even advanced illness does not free the
aberrant drug- and regulations ● Reassess and diagnose (addiction, other clinician from the requirement of
related Identification of patient needing psychiatric disorder, pseudoaddiction, family compliance with laws and regulations
behaviors additional management issues, criminal intent)
● Stop prescribing if diversion into the illicit
marketplace is discovered; otherwise, consider
restructuring therapy to improve control and obtain
consultative help as needed
Document and Risk assessment and Document It is also valuable to openly discuss the
communicate management should be ● Plan for monitoring and education of patient and need for universal risk management with
viewed as integral to safe family other clinicians to reduce the risk of
and effective prescribing ● Monitoring of drug-related behavior on a regular stigmatizing patients
basis
● Response should aberrant behavior occur

Adapted.8

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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
 Principles of Opioid Use in Cancer Pain

pain in populations with active cancer drives an imperative to follow
best practices. These practices are widely accepted, notwithstanding
the ongoing need for more research to provide comparative and
long-term data pertinent to current therapies and novel treatment
strategies for refractory pain.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant
or Advisory Role: None Stock Ownership: None Honoraria: Russell K.
Portenoy, Grupo Ferrer Pharmaceuticals Research Funding: None
Expert Testimony: None Patents, Royalties, and Licenses: None Other
Remuneration: None

Although all authors completed the disclosure declaration, the following AUTHOR CONTRIBUTIONS
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under Conception and design: Russell K. Portenoy
consideration in this article. Certain relationships marked with a “U” are Manuscript writing: All authors
those for which no compensation was received; those relationships marked Final approval of manuscript: All authors

REFERENCES
1. Goudas LC, Bloch R, Gialeli-Goudas M: The
epidemiology of cancer pain. Cancer Invest 23:182-
190, 2005
2. Caraceni A, Hanks G, Kaasa S, et al: Use of
opioid analgesics in the treatment of cancer pain:
Evidence-based recommendations from the EAPC.
Lancet Oncol 13:e58-e68, 2012
3. Dy SM, Asch SM, Naeim A, et al: Evidence-
based standards for cancer pain management. J Clin
Oncol 26:3879-3885, 2008
4. Koyyalagunta D, Bruera E, Solanki DR, et al: A
systematic review of randomized trials on the effec-
tiveness of opioids for cancer pain. Pain Physician
15:ES39-ES58, 2012
5. World Health Organization: Cancer Pain Re-
lief. Geneva, Switzerland, World Health Organiza-
tion, Office of Publications, 1986
6. Deandrea S, Montanari M, Moja L, et al:
Prevalence of undertreatment in cancer pain: A
review of published literature. Ann Oncol 19:1985-
1991, 2008
7. Breuer B, Fleishman SB, Cruciani RA, et al:
Medical oncologists’ attitudes and practice in cancer
pain management: A national survey. J Clin Oncol
29:4769-4775, 2011
8. Portenoy RK: Treatment of cancer pain. Lan-
cet 377:2236-2247, 2011
9. Pasternak GW: Opioids and their receptors:
Are we there yet? Neuropharmacology [epub ahead
of print on April 26, 2013]
10. Lötsch J, Rohrbacher M, Schmidt H, et al: Can
extremely low or high morphine formation from
codeine be predicted prior to therapy initiation? Pain
144:119-124, 2009
11. Quigley C, Joel S, Patel N, et al: Plasma
concentrations of morphine, morphine-6-glucuronide
and morphine-3-glucuronide and their relationship
with analgesia and side effects in patients with
cancer-related pain. Palliat Med 17:185-190, 2003
12. Dean M: Opioids in renal failure and dialysis
patients. J Pain Symptom Manage 28:497-504,
2004
13. Ahmedzai S, Brooks D: Transdermal fentanyl
versus sustained-release oral morphine in cancer
pain: Preference, efficacy, and quality of life—The
TTS-Fentanyl Comparative Trial Group. J Pain Symp-
tom Manage 13:254-261, 1997
14. Tassinari D, Sartori S, Tamburini E, et al:
Transdermal fentanyl as a front-line approach to
moderate-severe pain: A meta-analysis of random-
ized clinical trials. J Palliat Care 25:172-180, 2009
15. Tassinari D, Drudi F, Rosati M, et al: Transder-
mal opioids as front line treatment of moderate to
severe cancer pain: A systemic review. Palliat Med
25:478-487, 2011
16. Eap CB, Buclin T, Baumann P: Interindividual
variability of the clinical pharmacokinetics of metha-
done: Implications for the treatment of opioid de-
pendence. Clin Pharmacokinet 41:1153-1193, 2002
17. Weschules DJ, Bain KT: A systematic review
of opioid conversion ratios used with methadone for
the treatment of pain. Pain Med 9:595-612, 2008
18. Cruciani RA, Sekine R, Homel P, et al: Mea-
surement of QTc in patients receiving chronic
methadone therapy. J Pain Symptom Manage 29:
385-391, 2005
19. Kapur BM, Hutson JR, Chibber T, et al: Meth-
adone: A review of drug-drug and pathophysiological
interactions. Crit Rev Clin Lab Sci 48:171-195, 2011
20. Mercadante S, Porzio G, Ferrera P, et al: Low
doses of transdermal buprenorphine in opioid-naive
patients with cancer pain: A 4-week, nonrandom-
ized, open-label, uncontrolled observational study.
Clin Ther 31:2134-2138, 2009
21. Apolone G, Corli O, Negri E, et al: Effects of
transdermal buprenorphine on patients-reported
outcomes in cancer patients: Results from the Can-
cer Pain Outcome Research (CPOR) Study Group.
Clin J Pain 25:671-682, 2009
22. Poulain P, Denier W, Douma J, et al: Efficacy
and safety of transdermal buprenorphine: A random-
ized, placebo-controlled trial in 289 patients with
severe cancer pain. J Pain Symptom Manage 36:
117-125, 2008
23. Davis MP: Twelve reasons for considering
buprenorphine as a frontline analgesic in the man-
agement of pain. J Support Oncol 10:209-219, 2012
24. Wedam EF, Bigelow GE, Johnson RE, et al:
QT-interval effects of methadone, levomethadyl,
and buprenorphine in a randomized trial. Arch Intern
Med 167:2469-2475, 2007
25. Wilder-Smith CH, Schimke J, Osterwalder B,
et al: Oral tramadol, a mu-opioid agonist and mono-
amine reuptake-blocker, and morphine for strong
cancer-related pain. Ann Oncol 5:141-146, 1994
26. Leppert W: Tramadol as an analgesic for mild
to moderate cancer pain. Pharmacol Rep 61:978-
992, 2009
27. Mercadante S, Porzio G, Aielli F, et al: Opioid
switching from and to tapentadol extended release
in cancer patients: Conversion ratio with other opi-
oids. Curr Med Res Opin 29:661-666, 2013
28. Ripamonti CI, Bareggi C: Pharmacology of
opioid analgesia: Clinical principles, in Bruera EB,
Portenoy RK (eds): Cancer Pain: Assessment and
Management. New York, NY, Cambridge University
Press, 2010 pp. 195-229
29. Mercadante S, Villari P, Ferrera P, et al: Opti-
mization of opioid therapy for preventing incident
pain associated with bone metastases. J Pain Symp-
tom Manage 28:505-510, 2004
30. Walsh D, Tropiano PS: Long-term rectal ad-
ministration of high-dose sustained-release mor-
phine tablets. Support Care Cancer 10:653-655,
2002
31. Wilcock A, Jacob JK, Charlesworth S, et al:
Drugs given by a syringe driver: A prospective
multicentre survey of palliative care services in the
UK. Palliat Med 20:661-664, 2006
32. Thomas JR, Wallace MS, Yocum RC, et al:
The INFUSE-Morphine study: Use of recombinant
human hyaluronidase (rHuPH20) to enhance the
absorption of subcutaneously administered mor-
phine in patients with advanced illness. J Pain
Symptom Manage 38:663-672, 2009
33. Thomas JR, Yocum RC, Haller MF, et al: The
INFUSE-Morphine IIB study: Use of recombinant
human hyaluronidase (rHuPH20) to enhance the
absorption of subcutaneous morphine in healthy
volunteers. J Pain Symptom Manage 38:673-682,
2009
34. Mace SE, Harb G, Friend K, et al: Cost-
effectiveness of recombinant human hyaluronidase-
facilitated subcutaneous versus intravenous rehydration
in children with mild to moderate dehydration. Am J
Emerg Med 31:928-934, 2013
35. Mercadante S, Portenoy RK: Opioid poorly-
responsive cancer pain: Part 3. Clinical strategies to
improve opioid responsiveness. J Pain Symptom
Manage 21:338-354, 2001
36. Reddy A, Yennurajalingam S, Pulivarthi K, et
al: Frequency, outcome, and predictors of success
within 6 weeks of an opioid rotation among outpa-
tients with cancer receiving strong opioids. Oncolo-
gist 18:212-220, 2013
37. Knotkova H, Fine PG, Portenoy RK: Opioid
rotation: The science and limitations of the equian-
algesic dose table. J Pain Symptom Manage 38:426-
439, 2009
38. Fine PG, Portenoy RK, Ad Hoc Expert Panel
on Evidence Review and Guidelines for Opioid Ro-
tation: Establishing “best practices” for opioid rota-
tion: Conclusions of an expert panel. J Pain
Symptom Manage 38:418-425, 2009
39. Davies A, Buchanan A, Zeppetella G, et al:
Breakthrough cancer pain: An observational study of
1000 European oncology patients. J Pain Symptom
Manage 46:619-628, 2013

www.jco.org © 2014 by American Society of Clinical Oncology 1669

Downloaded from jco.ascopubs.org by Rafael Rosell on June 12, 2014 from 190.157.125.175
Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

40. Deandrea S, Corli O, Consonni D, et al: Prev-
alence of breakthrough cancer pain: A systematic
review and a pooled analysis of published literature.
J Pain Symptom Manage [epub ahead of print on
June 21, 2013]
41. Portenoy RK, Bruns D, Shoemaker B, et al:
Breakthrough pain in community-dwelling patients
with cancer pain and noncancer pain, part 2: Impact
on function, mood, and quality of life. J Opioid
Manag 6:109-116, 2010
42. Caraceni A, Davies A, Poulain P, et al: Guide-
lines for the management of breakthrough pain in
patients with cancer. J Natl Compr Canc Netw
11:S29-S36, 2013
43. Davies AN, Dickman A, Reid C, et al: The man-
agement of cancer-related breakthrough pain: Recom-
mendations of a task group of the Science Committee of
the Association for Palliative Medicine of Great Britain
and Ireland. Eur J Pain 13:331-338, 2009
44. Zeppetella G: Evidence-based treatment of
cancer-related breakthrough pain with opioids.
J Natl Compr Canc Netw 11:S37-S43, 2013
45. Jandhyala R, Fullarton JR, Bennett MI: Effi-
cacy of rapid-onset oral fentanyl formulations vs.
oral morphine for cancer-related breakthrough pain:
A meta-analysis of comparative trials. J Pain Symp-
tom Manage 46:573-580, 2013
1670 © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org by Rafael Rosell on June 12, 2014 from 190.157.125.175
Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Portenoy and Ahmed
46. Holzer P, Ahmedzai SH, Niederle N, et al: Opioid-
induced bowel dysfunction in cancer-related pain:
Causes, consequences, and a novel approach for its
management. J Opioid Manag 5:145-151, 2009
47. Becker G, Galandi D, Blum HE: Peripherally
acting opioid antagonists in the treatment of opiate-
related constipation: A systematic review. J Pain
Symptom Manage 34:547-565, 2007
48. Ford AC, Brenner DM, Schoenfeld PS: Effi-
cacy of pharmacological therapies for the treatment
of opioid-induced constipation: Systematic review
and meta-analysis. Am J Gastroenterol 108:1566-
1574, 2013
49. Stone P, Minton O: European Palliative Care
Research collaborative pain guidelines: Central side-
effects management—What is the evidence to sup-
port best practice in the management of sedation,
cognitive impairment and myoclonus? Palliat Med
25:431-441, 2011
50. Walker JM, Farney RJ, Rhondeau SM, et al:
Chronic opioid use is a risk factor for the develop-
ment of central sleep apnea and ataxic breathing.
J Clin Sleep Med 3:455-461, 2007
51. Rhodin A, Stridsberg M, Gordh T: Opioid
endocrinopathy: A clinical problem in patients with
chronic pain and long-term oral opioid treatment.
Clin J Pain 26:374-380, 2010
■ ■ ■
52. Chu LF, Angst MS, Clark D: Opioid-induced
hyperalgesia in humans: Molecular mechanisms
and clinical considerations. Clin J Pain 24:479-496,
2008
53. Bannister K, Dickenson AH: Opioid hyperalge-
sia. Curr Opin Support Palliat Care 4:1-5, 2010
54. Katz NP, Adams EH, Benneyan JC, et al:
Foundations of opioid risk management. Clin J Pain
23:103-118, 2007
55. Kuehn BM: Opioid prescriptions soar: In-
crease in legitimate use as well as abuse. JAMA
297:249-251, 2007
56. Extended-Release (ER) and Long-Acting (LA) Opi-
oid Analgesics Risk Evaluation and Mitigation Strategy
(REMS). http://www.fda.gov/downloads/Drugs/
DrugSafety/PostmarketDrugSafetyInformationfor
PatientsandProviders/UCM311290.pdf
57. Savage SR, Joranson DE, Covington EC, et al:
Definitions related to the medical use of opioids:
Evolution towards universal agreement. J Pain
Symptom Manage 26:655-667, 2003
58. Portenoy RK: Acute and chronic pain, in Ruiz
P, Strain E (eds): Lowinson and Ruiz’s Substance
Abuse: A Comprehensive Textbook (ed 5). Philadel-
phia, PA, Lippincott, Williams & Wilkins, 2011, pp
695-720
JOURNAL OF CLINICAL ONCOLOGY