Cancer Pain Management With Opioids - Optimizing Analgesia - UpToDate

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Cancer pain management with opioids: Optimizing

analgesia
Authors: Russell K Portenoy, MD, Zankhana Mehta, MD, Ebtesam Ahmed, PharmD, MS
Section Editor: Janet Abrahm, MD
Deputy Editor: Diane MF Savarese, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2019. | This topic last updated: Jun 06, 2019.
INTRODUCTION
Opioids are widely used for treatment of pain in patients with cancer because of their safety,
multiple routes of administration, ease of titration, reliability, and effectiveness for all types of pain
(ie, somatic, visceral, neuropathic). Although neuropathic pain may be more difficult to treat, a
favorable response to opioid-based analgesia is often possible. (See "Assessment of cancer
pain", section on 'Inferred pathophysiology (types of cancer pain)'.)
Opioids are also potentially abusable drugs. The public health consequences of opioid abuse drive
the imperative that all physicians assume responsibility for risk management when these drugs
are prescribed for legitimate medical purposes. These issues are discussed elsewhere. (See
"Cancer pain management: General principles and risk management for patients receiving
opioids", section on 'Risk assessment and management for patients receiving opioids'.)
This topic review will cover the use of opioids for cancer-related pain, with an emphasis on
optimizing analgesia and minimizing side effects. Assessment of cancer pain, a review of specific
cancer pain syndromes, general principles of cancer pain management, an overview of risk
management in patients treated with opioids, prevention and management of opioid side effects,
the clinical use of non-opioid analgesics (including nonsteroidal antiinflammatory drugs [NSAIDs]
and adjuvant analgesics), nonpharmacologic methods of cancer pain management, management
of acute pain (eg, from a new injury or surgical procedure) in the patient chronically using opioids,
and issues surrounding pain management in the last weeks of life are covered elsewhere:
● (See "Assessment of cancer pain".)

● (See "Overview of cancer pain syndromes".)
https://www.uptodate.com/contents/cancer-pain-management-with-opioids-optimizing-analgesia/print 1/50
● (See "Cancer pain management: General principles and risk management for patients
receiving opioids".)
● (See "Prevention and management of side effects in patients receiving opioids for chronic
pain".)
● (See "Cancer pain management: Use of acetaminophen and nonsteroidal antiinflammatory
drugs".)
● (See "Cancer pain management: Adjuvant analgesics (coanalgesics)".)
● (See "Psychological, rehabilitative, and integrative therapies for cancer pain".)
● (See "Cancer pain management: Interventional therapies".)
● (See "Management of acute pain in the patient chronically using opioids".)
OPIOID DRUGS USED IN CANCER PAIN MANAGEMENT
Mechanism of action — Opioids act by binding to specific receptors, the best characterized of
which are the mu, kappa, and delta receptors. These receptors are present in tissues throughout
the body, including both the peripheral and central nervous systems.
Based upon their effects on the mu receptor, opioids are conventionally divided into pure agonists,
agonist-antagonists (of which there are two subtypes: partial agonists and mixed agonist-
antagonists), and pure antagonists (table 1). Mu receptor antagonists have no intrinsic analgesic
properties; they are used to prevent or reverse opioid effects. (See "Prevention and management
of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel
dysfunction'.)
With few exceptions, the management of chronic cancer pain usually involves the long-term
administration of pure mu receptor agonists (table 2 and table 3). However, several of the agonist-
antagonist drugs are commercially available in the United States and other countries, and at least
one, buprenorphine, is used for treatment of cancer-related pain in some settings. Several other
centrally acting analgesics, including tramadol and tapentadol, have some mu agonist effects
mixed with other prominent mechanisms and also are used for cancer pain in some
circumstances.
Pure mu agonists commonly used for cancer pain
Morphine — Morphine is the prototype opioid drug for moderate to severe cancer pain on the
third step of the WHO analgesic ladder (figure 1) [1]. It is usually considered to be a standard for
comparison. In the original WHO guidelines, this preference for morphine was not based upon any
existing comparative data. Since then, randomized trials and systematic reviews have failed to
demonstrate the superiority of morphine over any other mu agonist (such as hydromorphone,
oxycodone, oxymorphone, fentanyl, or methadone) in terms of efficacy or tolerability [2-9].
Furthermore, there is very large intraindividual variation in the response to the different mu agonist
drugs and no way to predict whether a patient will have a more favorable balance between
analgesia and side effects when given morphine or one of the other drugs [2].
Accordingly, morphine should not be considered the “drug of choice,” but rather, just one of many
drugs that could be selected for chronic cancer pain. The decision to select one or another is often
based upon the experience of the clinician, prior experience of the patient, cost, dosing
implications of the formulation, and other factors.
Morphine has a short half-life, but it is available in multiple formulations, including immediate-
release tablets, oral liquid, suppository, solution for intravenous (IV) and subcutaneous (SC) use
(table 3), and modified-release drugs that provide continuous analgesia with once- or twice-daily
dosing (table 2). The short half-life formulations are preferred by some patients and also may be
useful for breakthrough pain when coadministered with a long-acting formulation. (See
"Assessment of cancer pain", section on 'Temporal assessment'.)
Regardless of the formulation, morphine is primarily metabolized in the liver and its metabolites
are renally excreted. Two active metabolites have been extensively studied, morphine-3-
glucuronide (M3G) and morphine-6-gluconoride (M6G) [10]. Preclinical data and limited human
studies suggest that M6G contributes to analgesic activity and M3G may be the cause of some of
the side effects that occur during morphine therapy, although this is not yet proven [11-14].
Metabolite concentration may be idiosyncratically high as a result of unknown but presumed

genetic factors, or more commonly, metabolite concentration may increase relative to the parent
compound (morphine) as a result of renal disease that reduces excretion of both glucuronides. If
this occurs, use of the drug may be associated with unanticipated potency or side effects.
Clinically, this means that morphine should be administered cautiously in the setting of renal
insufficiency, and if fluctuation in kidney function can be anticipated, morphine may not be the
preferred opioid given the risk of changes in effects and side effects as metabolite accumulation
occurs. (See 'Use in renal failure' below.)
Oxycodone, hydrocodone, hydromorphone, and oxymorphone — As with morphine,

hydromorphone, oxycodone, hydrocodone, and oxymorphone all have short half-lives and all are
available in multiple formulations. In the United States, all four of these drugs are available in long-
acting, modified-release formulations.
Oxycodone binds to both mu and kappa receptors, which may suggest some theoretical
advantage. Clinical studies have not substantiated systematic differences in efficacy or tolerability
compared with morphine or other mu agonists [15].
Multiple dosage forms are available for hydromorphone, including oral liquid, immediate release
tablet, extended release tablet, suppository, and solution for IV or SC use. The extended release
form of hydromorphone (Exalgo) is available in 8, 12, and 16 mg strengths, and is dosed once
daily. Caution must be used to avoid medication errors when prescribing this product, as 8 mg
tablets are also available as immediate-release hydromorphone tablets.
Hydromorphone is highly soluble in water [16] and a commercially available concentrated solution
(10 mg/mL) facilitates SC or IV administration of relatively high doses. Some clinicians prefer to
use hydromorphone in patients with renal insufficiency because its active, renally cleared
metabolites appear in relatively low concentration (compared with morphine) and may be unlikely
to cause unanticipated effects. (See 'Use in renal failure' below.)
The analgesic efficacy of oxymorphone is comparable to other opioids [17]. It has a relatively low
propensity to release histamine, a characteristic also shared with fentanyl. At least in theory, this
may reduce the risk of pruritus or urticaria, although there is no evidence that this difference is
clinically relevant.
A long-acting formulation of the drug, Opana ER, was voluntarily withdrawn from the United States
market in July 2017 at the request of the US Food and Drug Administration (FDA) because of
concerns that the benefits of the drug were outweighed by the risks related to continued injection
abuse of the drug, despite a reformulation in 2012 intended to make the drug resistant to physical
and chemical manipulation [18,19]. There are generic extended-release oxymorphone products
that remain on the market at present.
Short-acting hydrocodone is only available in the United States in combination with

acetaminophen. The amount of the nonopioid constituent limits use of these short-acting
combinations to relatively opioid-naïve patients with moderate pain.
A long-acting formulation of single entity hydrocodone (Zohydro ER) was approved in the United
States in October 2013 for the management of pain severe enough to require daily, around-the-
clock, long-term treatment and for which alternative treatment options are inadequate. It is
classified as a Schedule II controlled substance, requiring a written prescription, and cannot be
refilled. Although analgesic efficacy has been shown in a placebo-controlled trial conducted in
patients with chronic low back pain [20], the only data addressing efficacy in cancer populations
are from observational studies [21]. While the drug was initially approved without abuse-deterrent
properties, it now incorporates excipients that form a viscous gel when the capsules are crushed
or dissolved [22]. A second extended release abuse-deterrent hydrocodone tablet formulation,
Hysingla ER, is also available.
Fentanyl — Fentanyl is a highly lipophilic opioid that may be used parenterally or in

formulations developed for transdermal or oral transmucosal delivery. The transdermal formulation
is used for chronic pain. Both the non-oral route and the relatively infrequent dosing (every two to
three days for transdermal fentanyl) are considered advantages by some patients. Although data
from clinical trials about the potential for a relatively reduced risk of constipation from transdermal
fentanyl are conflicting [23-26], three meta-analyses have found a significant advantage for
transdermal fentanyl over sustained release oral morphine in terms of this side effect [27-29].
Fentanyl may be preferred over morphine in patients with renal insufficiency due to lack of active
metabolites.
Exposing the patch to heat (eg, an increase in body temperature, use of a heating pad or warming
blanket during surgery) may cause an unintentional increase in systemic fentanyl absorption,
which may increase the risk of respiratory depression. In addition, fentanyl patches contain metal,
which can pose a risk for local skin burn during magnetic resonance imaging (MRI) [30].
Physicians should advise patients to remove the patch before an MRI procedure and replace it
after completion of the scan. (See "Patient evaluation for metallic or electrical implants, devices, or
foreign bodies before magnetic resonance imaging", section on 'Drug infusion pumps and
patches'.)
Rapid-onset transmucosal preparations of fentanyl are discussed below. (See 'Management of

breakthrough pain' below.)
Levorphanol — Levorphanol is distinguished by its relatively long half-life (approximately 12 to

16 hours). Experience in the use of this drug is relatively limited in the US, but it should be viewed
as another option for the treatment of cancer pain, particularly when other mu agonists have not
been well tolerated or are unavailable.
Methadone — Methadone is a mu agonist opioid, but it has a unique pharmacology that

presumably underlies both the observation that some patients experience a surprising degree of
analgesia after being switched to a relatively low dose and the fact that others experience
unanticipated toxicity [31-33]. At least one controlled trial has shown that methadone is equally
effective to morphine for cancer pain [34]. Among the potential benefits of methadone use are its
low cost and long duration of action; it is the only long acting opioid available in a liquid formulation
[35,36]. Because only approximately 20 percent of a dose is eliminated unchanged by the kidneys
and there are no active metabolites, methadone, when dosed appropriately (see below), also may
be a useful drug in patients with kidney disease (see 'Use in renal failure' below).
The fact that methadone is effective in treating the opioid craving that occurs in those with opioid
addiction has been used as a rationale for the use of this drug in those patients who develop
aberrant drug-related behavior when given another mu agonist for cancer pain and for those who
are a high risk of these behaviors before starting therapy.
These potential benefits of methadone do not alter the recommendation that the drug should be
prescribed only by those who are familiar with its pharmacology and can employ safe prescribing
practices. Guidelines for safe administration must be followed to reduce the risk of unintentional
overdose. Clinicians who have questions about these guidelines or who lack experience may wish
to seek assistance from a consultant before prescribing this drug. The pertinent issues are
summarized as follows:
● Methadone has a variable half-life, which averages approximately 24 hours but ranges from
12 hours to almost one week [31]. Since five to six half-lives are required before steady state
plasma concentrations are approached, the time required before a methadone regimen can
be considered stable varies from several days to several weeks. During the period when
plasma levels are rising toward steady state levels, the patient must be considered at risk for
unintentional overdose from accumulation in plasma.
Due to highly variable and prolonged terminal half-life, methadone has the highest risk of
among opioids of accumulation and overdosage during initial titration to effect, and during
dose adjustment in chronic use.
● Perhaps more challenging, methadone is marketed in most of the world as a racemate

containing a 1:1 mixture of the d- and the l-isomer. The d-isomer is a relatively potent N-
methyl-D-aspartate (NMDA) inhibitor and not an opioid. NMDA antagonism is associated with
nonopioid analgesia and with reversal of opioid tolerance. These effects may explain the
observation that methadone can be far more potent than would be expected from the
equianalgesic dose table (table 3), particularly when administered to patients with substantial
prior opioid exposure. Concern about this unexpected potency must be addressed by
selecting a cautious initial dose when switching from another drug to methadone (see below).
● Methadone can prolong the QTc interval [37-39], a phenomenon that predisposes to a life-
threatening cardiac arrhythmia, torsades du pointe. Although the clinical importance of this
effect continues to be controversial, it is prudent to check an ECG prior to therapy in most
patients. The drug should be used very cautiously in those with a QTc interval >450
milliseconds (ms; by considering interventions that may treat any potentially reversible causes
of QTc prolongation, such as hypokalemia) and generally should not be used if the QTc
interval exceeds 500 milliseconds. A repeat ECG is prudent in all patients, particularly if the
total daily dose reaches 100 mg [40], and repeated monitoring is essential in those patients
predisposed to QTc prolongation (eg, those taking other drugs with this effect (table 4) and
those with existing significant heart disease). (See "Acquired long QT syndrome: Definitions,
causes, and pathophysiology", section on 'Medications'.)
● Methadone is metabolized by CYP3A4 and CYP2B6 isoenzymes, and to a lesser extent, by

other CYPs (2C19, 2C9, 2D6); drugs that function as inhibitors of CYP3A4 may increase
methadone levels, and patients receiving concomitant treatment with one of these inhibitors
should have methadone doses reduced. On the other hand, patients undergoing concomitant
therapy with a CYP3A4 or 2B6 inducer may experience decreased methadone levels and
reduced efficacy or withdrawal. A table listing several known inducers and inhibitors of
CYP3A4 is provided (table 5). Note that some drugs identified as strong CYP3A4 inhibitors
can decrease methadone exposure (ie, opposite of expected effect) by an uncertain
mechanism (eg, ritonavir boosted antiretroviral regimens including lopinavir-ritonavir,
saquinavir ritonavir, darunavir-ritonavir, tipranavir-ritonavir). Thus, interactions should be
carefully analyzed whenever drug therapy with methadone is adjusted. The Lexicomp drug
interactions (Lexi-Interact) tool is available within UpToDate for this purpose.
Pure mu agonists rarely used for cancer pain — Within the large group of pure mu agonist
drugs, there are some that are of historical importance but are now rarely, if ever, used for cancer
pain.
Codeine — Codeine, for example, was conventionally considered to be a first-line agent for the
treatment of mild to moderate pain in patients with limited opioid exposure [2]. The World Health
Organization (WHO) analgesic ladder for treatment of cancer pain (figure 1) [1], first published in
the 1980s, referred to this drug as the prototype “weak” or “mild” opioid, but now this designation
is understood to be pharmacologically inappropriate. Although it is intended to treat mild to
moderate pain in the patient with limited to no opioid exposure, there is very limited evidence of a
positive therapeutic index in cancer pain [41], and any pure mu agonist can be used for this
purpose if the dose is selected appropriately.
This approach is endorsed in guidelines for cancer pain management from the National
Comprehensive Cancer Network (NCCN) and other organizations, including the European
Association for Palliative Care; it effectively eliminates the second “rung” of the analgesic ladder
approach (figure 1) and reflects attempts to update the original WHO guideline [42]. One study
found that low-dose morphine (up to 30 mg daily) reduces pain significantly as compared with
codeine (or tramadol) with or without acetaminophen in patients with moderate cancer pain, with
similar tolerability and an earlier effect [43].
Codeine is also available in combination with acetaminophen. However, the maximal daily dose of
acetaminophen (current recommendations put this figure at 3.2 g/day, lower in those without
known liver disease or risk factors for liver disease) effectively limits the amount of codeine that
can be administered with this combination product. (See "Cancer pain management: Use of
acetaminophen and nonsteroidal antiinflammatory drugs".)
The broad acceptance of codeine as a WHO analgesic ladder (figure 1) step 2 drug has also
come under scrutiny as a result of new information about genetic variation in metabolism. The
analgesic efficacy of codeine requires conversion to morphine via the CYP2D6 isoenzyme of the
P450 hepatic enzyme system. CYP2D6 is highly polymorphic, with over 90 known allelic variants.
Five to 10 percent of patients inherit a slow metabolizer phenotype, and they derive only limited or
no therapeutic benefit from codeine because it will not be converted to its active moiety.
Conversely, patients who are ultra-rapid metabolizers based on CYP2D6 genotype may have
higher than expected morphine levels (an initial “overdose”), with more side effects and a shorter
than expected duration of pain control. Similar effects have been described in patients receiving
hydrocodone and oxycodone but without the presumed clinical relevance perceived with codeine
[44,45].
This variation in population genetics and the inability to predict analgesic effects prior to
administration [46] suggest that codeine should not be among the preferred drugs for cancer pain
management. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug
metabolism'.)
Meperidine — Meperidine is not preferred for use in the cancer pain population. It is
metabolized into a compound (normeperidine) that is relatively toxic, and associated with
tremulousness, delirium and seizures. Accumulation of the metabolite is most likely to occur
during repeated administration, and dose escalation, and in the setting of impaired elimination
caused by renal insufficiency. It is safer to select an alternative mu agonist for the management of
chronic pain.
Mixed-mechanism drugs: Tramadol and tapentadol — Tramadol and tapentadol are centrally
acting analgesics whose mode of action is based both on the mu receptor binding and monoamine
(serotonin and norepinephrine) reuptake blockade. Tramadol is widely used in some countries for
moderate to severe cancer pain as an alternative to other opioids [47,48], but it is not used as
commonly in the United States. Evidence is limited comparing either drug with other opioids in
terms of either efficacy or tolerability in patients with cancer-related pain:
● A Cochrane review of four randomized trials of tapentadol compared with either placebo or an
active control in 1029 adults with moderate to severe cancer pain concluded that there were
insufficient data for pooling and statistical analysis of the four trials [49]. Overall, there was
low quality evidence that tapentadol was no more or no less effective for pain relief than
morphine or oxycodone, and there was no advantage of tapentadol in terms of serious
adverse events.
● Similarly, a Cochrane review of 10 studies comparing tramadol with either placebo or an

active control in 958 adults with moderate to severe cancer pain concluded that there was
limited, very low-quality evidence from randomized trials that tramadol produces pain relief in
some adults with pain due to cancer, and very low-quality evidence that it is not as effective
as morphine [50].
The place of these drugs in managing moderate to severe cancer pain remains unclear.
Mixed agonist-antagonist drugs
Buprenorphine — Buprenorphine is available as a treatment for opioid addiction and as a

treatment for pain. (See "Pharmacotherapy for opioid use disorder", section on 'Buprenorphine'.)
Buprenorphine has a complex pharmacology and is variably described in the literature as a partial
agonist at the mu opioid receptor, one with high affinity but low activity, with additional antagonism
at the kappa receptor and other opioid receptors. As a partial agonist, it may have a ceiling effect
for analgesia, but clinical experience with higher doses for the treatment of pain is limited, and the
extent to which there is a clinically meaningful ceiling effect is uncertain. As a high-affinity partial
agonist, buprenorphine has the ability to induce withdrawal if it is administered to patients who are
already physically dependent on a pure mu agonist drug, and this complicates the management of
patients who are switched to this drug when already physically dependent on another opioid.
However, it may be of use in relatively opioid-naïve cancer patients. (See 'Other drugs' below.)
Transdermal buprenorphine has been licensed in Europe and is commonly prescribed for chronic
pain. There is less experience with transdermal buprenorphine in the United States, where a patch
formulation became available in 2010 (Butrans 5, 10, or 20 mcg/hour, all intended for seven-day
use) for treatment of chronic pain. The transdermal patch carries a warning against exceeding 20
mcg/hour due to the risk of QT prolongation. A long-acting (daily or twice-daily administration)
buprenorphine buccal film is also available in the United States.
Experience with this drug in the management of cancer pain is limited; however, anecdotal
reports, a few small prospective uncontrolled studies, and at least two small placebo-controlled
randomized trials (conducted over a period of approximately two weeks) support at least short-
term effectiveness and safety in patients with severe cancer-related pain [51-55]. Few comparative
studies have been performed against other long-acting opioids, and the quality of the evidence
from two such trials is uncertain [56,57]. Nonetheless, a 2009 consensus statement from an
international panel with expertise in palliative care and pain treatment endorsed the use of
transdermal buprenorphine where available [58].
Given the limited evidence, the doses available in the United States, and the need for special
considerations when using the drug in those who are already physically dependent on a pure mu
agonist opioid, it is reasonable to consider buprenorphine only in those who are relatively opioid
naïve, typically patients with new-onset, relatively moderate cancer pain. In support of this, a 2016
abridged Cochrane review concluded, given the limited quality of the evidence for patients with
cancer pain, that buprenorphine should not be considered a routine first-line option for opioid
therapy. One setting in which buprenorphine may be particularly useful is in a patient with
preexisting renal impairment [59,60]. (See 'Use in renal failure' below.)
A long-acting (daily or twice-daily administration) buprenorphine buccal film is also available in the
United States.
Other drugs — Drugs of the mixed agonist-antagonist group (butorphanol, dezocine,

pentazocine and nalbuphine) are generally not preferred for cancer pain management. This is
because of a ceiling effect for analgesia, and the capacity to induce abstinence when administered
to patients already receiving other opioids of the mu agonist class.
PRACTICAL CONSIDERATIONS IN OPIOID USE
Prescribing restrictions and risk management — Medications such as opioids with the
potential for abuse and addiction are regulated, with restrictions on whether and how they can be
prescribed. In the United States, these drugs are designated “controlled substances” under a
federal law known as the Controlled Substances Act (table 6). Issues in risk management when
these drugs are prescribed are addressed elsewhere. (See "Cancer pain management: General
principles and risk management for patients receiving opioids", section on 'Risk assessment and
management for patients receiving opioids'.)
Selecting the opioid — Although efforts have been made to analyze the literature on opioid
comparative efficacy and effectiveness [61], the clinical relevance of the data available precludes
an evidence-based approach to opioid selection. Accordingly, recommendations continue to be
based on clinical experience. Conventionally, patients who are opioid naïve and have pain severe
enough to warrant opioid therapy have been offered one of the opioid-nonopioid combination
products or one of the pure mu agonists at a low initial dose. If acetaminophen-oxycodone is used,
the dose of the opioid usually is 5 mg per tablet; a lower dose (2.5 mg per tablet) should be
considered in older or very frail adults (table 7). (See "Palliative care: Issues specific to geriatric
patients", section on 'Approach to treatment'.)
If acetaminophen-hydrocodone is used, the usual dose of the opioid is 5 to 7.5 mg per tablet. The
initial prescription usually is one to two tablets every three hours, as needed. 2.5 and 10 mg
hydrocodone-acetaminophen combinations are also available. Alternatively, the patient who is
relatively opioid naïve and who has moderate to severe pain can receive a single-entity pure mu
agonist at a low dose. Options include morphine (5 to 10 mg every three to four hours), oxycodone
(2.5 to 5 mg every three to four hours), hydromorphone (2 to 4 mg every three to four hours), or
transdermal fentanyl (12 mcg/hour every 72 hours). (See 'Pure mu agonists commonly used for
cancer pain' above.)
If a patient is given a short-acting drug and needs several doses per day (or if a bedtime dose
does not permit uninterrupted sleep through the night), a switch to a long-acting formulation is
commonly undertaken in an effort to improve convenience and adherence. There is no evidence
that any one of the commonly used, long-acting formulations that are available in the US, including
morphine, hydromorphone, oxycodone, oxymorphone, and fentanyl, is more likely to be effective
than any other [62]. Selection usually is determined by the patient's prior experience with opioids,
the clinician's experience, cost and availability, and formulation.
As noted, there is some evidence that transdermal fentanyl is less constipating than oral morphine
and the former drug may be preferred if constipation has been a challenging problem. If an oral
formulation is given, some patients prefer once-daily dosing, eg, with hydromorphone or morphine,
rather than twice-daily dosing.
Although methadone is far less costly and can be used effectively as a long-acting drug for cancer
pain (usually requiring dosing every six to eight hours, and sometimes as infrequently as every 8
to 12 hours for this purpose), the challenges inherent in the safe prescribing of this drug suggests
that it should be considered a first-line treatment option only by clinicians experienced in its use.
Otherwise, methadone is a second-line agent, to be tried only in the event that trials of one or
more of the other pure mu agonist drugs fail to provide an adequate balance between analgesia
and side effects. (See 'Methadone' above and 'Switching to methadone' below.)
Use in renal failure — As noted on the above sections, certain opioids should be used
cautiously in patients with renal failure [63-65].
● Meperidine (Demerol) is particularly dangerous, since its active metabolite, normeperidine,

accumulates with renal dysfunction or prolonged use at high doses. Normeperidine has a long
half-life and causes central nervous system (CNS) excitability. For this reason, meperidine is
not preferred for cancer pain management.
● Morphine is metabolized in part to a potent opioid metabolite, morphine-6-glucuronide, and a

metabolite, morphine-3-glucuronide, which is associated with neurotoxicity. Concerns have
been raised that these metabolites are renally excreted, and can accumulate and lead to
unanticipated changes in potency or side effects in patients with renal insufficiency [66].
However, the current evidence for neurotoxic effects in patients with renal impairment treated
with morphine consists of very-low-quality studies with conflicting findings [67]. Nevertheless,
morphine should be administered carefully in the setting of stable renal insufficiency and with
close monitoring for neurotoxic effects; if kidney function is changing, its use should be
reconsidered.
● Both codeine and tramadol can accumulate in patients with renal failure, extending their
effects.
Hydromorphone has active metabolites that are produced in relatively low concentration
(compared with morphine) and may be less likely to cause unanticipated effects in the setting of
renal insufficiency; however, they still can occur, particularly with higher doses [68-70].
Fentanyl and methadone lack active metabolites and could be considered in the setting of renal
insufficiency on this basis. However, the challenges of safe methadone prescribing speak against
the use of this drug in patients who may be metabolically unstable, and clinicians may prefer to
use either fentanyl or hydromorphone in patients with renal insufficiency. (See 'Methadone'
above.)
Buprenorphine is another option, at least for opioid-naïve patients [60,65]. (See 'Buprenorphine'
above.)
It should be noted that these recommendations are largely based upon pharmacokinetics and
clinical experience; there is very little high-quality clinical evidence to support opioid choice in
patients with renal impairment [65].
Use in liver failure — Most opioids are at least partially metabolized by the liver, complicating
their use in patients with liver failure [71]. However, safe prescribing of analgesics for patients with
chronic liver disease is possible as long as a few general guidelines are followed (table 8). In
general:
● Lower initial starting doses for most opioids are warranted in patients with liver failure, and
clinicians should be cautious prescribing opioids at “regular” dosing intervals until patients
have demonstrated an ability to tolerate the dosing interval. As the liver disease progresses,
prolonged dosing intervals may be needed.
● Codeine and meperidine should be avoided entirely in patients with liver failure. Codeine is a
prodrug that is converted to morphine via the CYP2D6 isoenzyme of the P450 hepatic
enzyme system; pain control may be compromised by diminished metabolism. In hepatic
disease, meperidine clearance is reduced, and the half-life is prolonged.
Management of breakthrough pain — Breakthrough pain is a transitory severe acute pain that
occurs on a background of chronic pain that is adequately controlled by an opioid regimen [72,73].
Given its high prevalence in patients with cancer pain, and its negative clinical consequences, a
treatment approach known as “rescue” dosing has become a widely accepted approach.
Management of acute pain (eg, from a new injury or surgical procedure) in patients chronically
using opioids for non-cancer pain is addressed in detail elsewhere. (See "Management of acute
pain in the patient chronically using opioids".)
Typically, a short-acting supplemental opioid is offered on an as needed basis for breakthrough

pain in conjunction with a fixed scheduled long-acting drug. Depending on the dose required and
other factors, the rescue drug may be a single entity oral formulation, such as immediate release
morphine, oxycodone, hydromorphone, or oxymorphone, or one of the combination products. A
typical dose chosen for rescue is 5 to 15 percent of the basal daily requirement of opioid [74]. (See
'Practical considerations in opioid use' above.)
For the typical oral rescue drugs like morphine, the dose should be titrated as the dose of the fixed
scheduled regimen changes, so that the rescue dose remains roughly proportional to the baseline
dose.
Breakthrough pain also may be targeted with one of the newer rapid-onset, transmucosal fentanyl
formulations, which are specifically indicated for cancer-related breakthrough pain. Six
formulations are now available in the United States: an oral transmucosal fentanyl lozenge (Actiq),
an immediate-release transmucosal tablet formulation (Abstral), an effervescent fentanyl buccal
tablet (Fentora), a nasal spray (Lazanda), and a sublingual spray (Subsys) (table 9). In the United
States, all of these products, including generics, have a mandatory shared risk evaluation and
mitigation strategy (REMS), the purpose of which is to reduce the risk of abuse and unintentional
overdose. To prescribe any of these drugs, physicians must complete online
education. Furthermore, each patient treated requires registration of the patient, physician, and
pharmacist. (See "Cancer pain management: General principles and risk management for patients
receiving opioids".)
Studies of these drugs have established the efficacy of transmucosal application, with an onset of
effect that is faster than that expected from oral formulations [75-81]. Comparative effectiveness
against one of the typical short-acting oral formulations has been determined for the nasal and
oral fentanyl formulations [76,78,82], and the more rapid onset of effect appears to be highly
favorable, at least for some patients. Sublingual fentanyl may also be preferred by patients over
subcutaneous morphine [83] Few studies have directly compared transmucosal formulations with
one another [84].
Due to cost and limited experience, the transmucosal drugs are generally considered only after a
patient has demonstrated a poor response to an oral rescue dose. Patients with very-rapid-onset
pain might also be considered for an early trial. Given the lack of comparative data, there are no
recommendations about which of the many formulations might be preferable.
Regardless of the formulation selected and in contrast to the oral rescue medications, the
recommended starting dose of transmucosal immediate-release fentanyl is the lowest or next-to-
lowest available dose. This recommendation is made because controlled trials have not confirmed
that a dose proportionate to the baseline dose is needed to observe effects. Dose titration usually
is needed.
Selecting the route of administration
Oral — The oral route is usually preferred for chronic treatment of cancer pain because of
convenience and flexibility. Many cancer patients require alternative routes of analgesic
administration at some time during the course of their illness.
In most patients, orally administered, immediate-release formulations have a peak analgesic effect
at 1 to 1.5 hours, while the analgesic peak with modified-release formulations is in approximately
three to five hours. Some of the immediate release opioids, such as morphine and oxycodone, are
also available in liquid formulations, which may be useful for patients with odynophagia or
dysphagia or who can only receive medications through feeding tubes.
Oral modified-release medications should never be crushed because of the potential for “dose
dumping” and acute toxicity. Several of the modified release opioids can “dose dump” if
coadministered with alcohol, which can dissolve the matrix in which the drug is embedded. It is
best to inform patients that alcohol consumption should be avoided during the hours around
administration of each dose.
Use of the oral route may not be feasible in patients with oral mucositis, dysphagia, bowel
obstruction, or severe nausea. Some of the modified release morphine formulations (eg, Avinza,
Kadian) are capsules that can be opened and sprinkled on food without changing the delivery
characteristics; this can permit the administration of a modified-release drug through a feeding
tube, if necessary, but the pellets can clog all but the largest feeding tubes. Liquid methadone may
be a better choice for those patients.
Transdermal — Transdermal fentanyl is widely used for chronic pain. Each transdermal patch
provides 48 to 72 hours of relatively stable drug delivery for most patients. (See 'Fentanyl' above.)
Transdermal fentanyl may be preferred over an orally administered opioid in the setting of poor
gastrointestinal tract absorption or dysphagia, or if constipation is an issue. Transdermal fentanyl
may also be preferred by patients who are distressed by the number of tablets required to manage
medical disorders and for those whose adherence to treatment would be improved by use of the
transdermal route.
Transdermal fentanyl may not be effective in patients lacking adequate adipose tissue over which
the patch can be placed. In such patients, without an adequate subcutaneous drug reservoir,
fentanyl serum levels may never become therapeutic, presumably because the drug is not
delivered to the blood as a continuous infusion and the liver metabolizes the drug as it is
presented to it. Patients with low albumin levels who have frequent infections are at risk for toxicity
from transdermal fentanyl because of sudden increases in the free fraction of fentanyl along with
increased absorption from the reservoir when the patient’s temperature exceeds 102 degrees FF.
Transdermal buprenorphine is available in some countries, including the United States. As

discussed, efficacy in cancer pain has been addressed in six randomized trials, in which
transdermal buprenorphine was compared with placebo, morphine, or transdermal fentanyl
[23,53,55,57,85,86]. Although efficacy is likely, the studies were not designed to address long-term
effectiveness, making the results difficult to interpret [87]. The available data suggest that
transdermal buprenorphine may be useful, as in patients who are relatively opioid naïve and do
not have severe pain requiring rapid dose titration; it is not generally considered first line due to
the limited experience. (See 'Buprenorphine' above.)
Rectal — Occasional patients are treated with rectal administration of an opioid [88]. In the
United States, short-acting rectal formulations are available for morphine (5, 10, 20, 30 mg rectal
suppositories), hydromorphone (3 mg) and oxymorphone (5 mg). In addition, there is limited
anecdotal experience in the rectal use of a long-acting modified-release formulation [89,90].
The potency of rectally administered opioids is believed to approximate oral dosing, but absorption
is variable and relative potency may be higher or lower than expected [90,91]. For this reason, a
switch from oral to rectal dosing is usually accompanied by a reduction in the equivalent dose.
(See 'Equianalgesic opioid dose conversion' below.)
Subcutaneous and intravenous administration — Among patients with a progressive illness

like cancer, it is commonplace for a pain regimen that was initially administered via an oral or
transdermal route to be switched, at least temporarily, to continuous intravenous (IV) or

subcutaneous (SC) infusion. The intramuscular route is not generally used because it is painful
and provides no pharmacological advantage.
Continuous SC infusion can be easily accomplished using a “butterfly” catheter inserted under the
skin of the chest wall or abdomen; the needle can remain in place for a week or more, and any
drug with an injectable formulation can be administered in this way [92]. Methadone is not
preferred via the SC route as it can act as an irritant to the skin.
In order to maintain the comfort of an infusion site, the SC infusion rate should not exceed 5
mL/hour. Higher volumes can be delivered, however, if hyaluronidase is added to the infusion. In
order to limit the total volume of injectate, hydromorphone may be chosen over fentanyl and
morphine because of its greater water solubility [93]; it is commercially available in a relatively
concentrated 10 mg/ml solution for injection.
Patients receiving continuous IV or SC infusion may benefit from access to intermittent

administration of a short-acting drug for breakthrough pain. The IV route has the most rapid onset
of action. When administered as an IV bolus, some drugs, such as fentanyl, have a peak onset
almost immediately, whereas other drugs, such as morphine, may require 15 to 30 minutes
because of the time required to penetrate the blood-brain barrier.
Patient-controlled analgesia — A pump with a patient-controlled analgesia (PCA) option

can be used to administer continuous infusion by either the IV or SC route, and thereby facilitate
the option of “rescue doses.” PCA devices are programmed for the size of the dose, the minimum
time between doses (lockout interval), and the cumulative dose allowed in one or four hours
(several times higher than the anticipated need).
Although safe and efficacious PCA settings for morphine, hydromorphone, and fentanyl are widely
accepted when this modality is used for acute postoperative pain, the settings are usually quite
different when PCA is selected for cancer pain. Patients typically have a prior opioid regimen that
is switched to an appropriate dose of a continuous infusion. The supplemental rescue dose
administered via the PCA pump is selected to be roughly in the range of 5 to 15 percent of the
total daily dose. In contrast to acute pain, the treatment of which often involves access to PCA
delivered doses every six to seven minutes, the so-called lockout period when PCA is used to
deliver rescue doses during chronic infusion may be longer, such as 10 to 20 minutes, although
there is substantial inter-institution variability.
Intrathecal and intraspinal administration — Properly selected patients can benefit from
more sophisticated pain management approaches, such as intraspinal opioid administration
(epidural or intrathecal, collectively called “neuraxial” analgesia) [94]. At least one randomized trial
comparing conventional analgesic therapy with neuraxial analgesia via an implanted
programmable pump in cancer patients with pain found that the intrathecal route yielded better
pain control and fewer side effects [95].
Patients whose pain has not responded to routine systemic therapy should be considered for
referral to a specialist in pain management for evaluation of this and other neuraxial techniques,
among other interventional strategies for pain management. (See "Cancer pain management:
Interventional therapies".)
Dose titration — Following selection of a starting dose, adjustment is almost always required to
optimize an opioid regimen and sustain its benefits over time. Dose individualization is the key to
optimizing the outcomes of opioid therapy [96-100].
Continuous or frequently recurrent pain is most effectively managed with a fixed schedule,
“around-the-clock” opioid regimen, which is usually combined with “as needed” rescue doses for
breakthrough pain. Dose titration to achieve adequate pain relief from a fixed scheduled regimen
is attainable in most cases.
Conventionally, dose titration is accomplished in one of two ways. The fixed scheduled dose can
be increased by 30 to 100 percent of the total dose taken in the prior 24 hour period (with the
percent increase informed by the severity of the pain, the degree of medical frailty or comorbidities
that may increase opioid risk, and the existing formulations). Alternatively, the fixed scheduled
dose can be increased by a daily amount that is determined by averaging the total amount of
supplemental rescue medication taken during the prior few days (adjusted for the estimated
equianalgesic potency, if needed (table 3 and table 10)). These step-wise methods of dose
escalation ensure safety as the dose is increased. Caution should be exercised in adding >50
percent of the total dose taken in prior days when the supplemental rescue medication is used for
incident pain only or procedure-related pain such as occurs during dressing changes. Such
patients will continue to require rescue doses and may become excessively somnolent in between
pain exacerbations.
As a general rule, the dose of an opioid can be increased until a favorable balance between
analgesia and side effects is obtained, or the patient develops intolerable and unmanageable side
effects. It is accepted best practice to continue dose escalation without regard to a maximum dose
unless troublesome side effects occur, observations suggest that dose incrementation will not be
able to control the pain, there is excessive pill burden, or some other event occurs that indicates
the need for an alternative strategy. Importantly, relatively higher doses (eg, those above 200 mg
of morphine per day or its equivalent) are not commonly needed to manage cancer pain. If titration
to a relatively high dose is pursued, the process should be accompanied by careful reassessment
to ensure that the drug still provides benefits and that the regimen is not compromised by subtle
toxicities or burdens associated with cost or number of tablets.
Ideally, the interval between dose escalations should be long enough to allow a new steady state
(which requires five to six half-lives, irrespective of the route or drug) to be approached following
each dose adjustment:
● Two to three days for the modified-release oral formulations.
● Three to six days for the transdermal patch.
● Although five days is usually sufficient to judge the full effect of a change in methadone dose,
the variability of this drug's half-life means that occasional patients will require much longer
periods (up to several weeks) to ensure that effects have become stable. (See 'Methadone'
above.)
For patients with severe pain, more rapid dose escalation is needed. However, when doses are
escalated at intervals shorter than those necessary to approach steady state (five to six half-lives),
there is a possibility of “overshooting.” In this phenomenon, the patient undergoing rapid dose
titration reports benefit, but continuation of the successful dose later results in toxicity as drug
levels continue to rise toward steady state.
When rapid dose titration is needed to address poorly controlled pain, the risk of overshooting
should be assessed. The risks are greater when the drug has a relatively long half-life (the
greatest concern is with methadone) or the patient is medically frail. In some cases, hospitalization
should be considered for the express purpose of monitoring aggressive escalation of the dose.
Hospitalization during a period of particularly intense pain, or “pain crisis,” is a medically
appropriate option for selected patents.
As the dose of the fixed schedule opioid regimen is increased, the dose of the “rescue” drug also
must be increased. In most cases, the dose of this short-acting medication should remain in the
range of 5 to 15 percent of the total daily dose [101]. The exception to this is found when using the
rapid-onset transmucosal fentanyl formulations, which may have effects at doses that are not
proportional to the fixed schedule dose [102]. In the case of these drugs, the starting dose should
be low and dose titration should ascend with the commercially available dose units, stopping at a
level associated with benefit. (See 'Management of breakthrough pain' above.)
As higher opioid doses are reached, there may be a temptation to apply excessive caution during
further titration. An understanding of the pharmacology of these drugs should provide the
reassurance necessary to avoid undertreatment, as illustrated by the following illustrative case.
A patient with slowly progressive breast cancer, who has undergone several periods of opioid
dose adjustment because of worsening pain, is taking long-acting oxycodone 240 mg twice daily
plus “rescue” doses consisting of five tablets of short-acting oxycodone 5 mg (25 mg per dose); on
each day, approximately four rescue doses are needed. She has no side effects except for
constipation, which has been controlled with laxatives. When her pain worsens again, she is
assessed, and in the absence of unmanageable side effects, the decision is made to further
escalate the dose. Her total daily dose of oxycodone has been 480 mg (long-acting) plus 100 mg
(rescue) or 580 mg. There are two approaches to dose increase:
● One approach to increasing the dose is to add 30 to 50 percent to the total daily dose (30
percent of 580 = 174). The largest oxycodone tablet is 80 mg, and an increase of 30 percent
can be easily accomplished by adding one 80 mg tablet to each of the fixed doses: a fixed
regimen of 320 mg twice daily. The rescue dose can be changed to 35 mg per dose at the
same time.
● The alternative approach, adding the total daily rescue dose, or 100 mg/day in this case, to
the fixed scheduled dose yields a more conservative outcome but still one in the range to be
useful.
Both strategies are appropriate and safe; any smaller increment is unlikely to be beneficial.
This case illustrates a typical pattern observed during long-term treatment of cancer pain. The
opioid dose is usually maintained for a prolonged time, unless there is progression in the pain-
producing pathology. Recurrent pain or the new occurrence of side effects necessitates a new
assessment, and often, another period of dose titration. Although the use of relatively high doses
requires careful reevaluation, the absolute dose of the opioid is inconsequential as long as the
balance between analgesia and side effects remains acceptable for the patient.
Pain that respond poorly to opioids alone — When a patient’s pain is poorly responsive to an
opioid, it might be related to the type of pain (neuropathic pain may not respond completely to
opioid therapy alone and may be better approached with adjuvant analgesics) or other issues,
such as a high propensity to develop side effects (eg, presence of preexisting cognitive
impairment, frail older adults). (See "Cancer pain management: Adjuvant analgesics
(coanalgesics)", section on 'Neuropathic pain'.)
Furthermore, most patients receiving opioids for cancer pain experience analgesia along with one
or more side effects. When side effects predominate and overwhelm the benefits produced by the
drug, the patient is said to have opioid poorly responsive pain [103,104]. Clinicians must be
attuned to this possibility, recognize it promptly, assess potential contributors (table 11), and be
prepared to offer an alternative strategy for pain management.
The initial steps include conducting a thorough pain assessment, including questions about
psychological and spiritual concerns. If substance abuse is suspected, a detailed history relevant
to substance abuse outcomes (nonadherence, addiction, and diversion) should be done. (See
"Cancer pain management: General principles and risk management for patients receiving
opioids", section on 'Risk assessment and management for patients receiving opioids'.)
A physical examination should be completed, and diagnostic studies ordered, as indicated.
If a potentially treatable etiology of the poorly responsive pain cannot be identified, and it is clear
that additional analgesic benefit is not being derived from dose escalation of a single opioid, a new
plan of care must be developed. This may involve any one of a large number of options (table 12)
[105], each of which must be evaluated in terms of benefit and burden, within the context of the
larger goals of care. Strategies for prevention and management of common opioid side effects are
covered elsewhere. (See "Prevention and management of side effects in patients receiving opioids
for chronic pain".)
Opioid rotation — A common approach to the management of poorly responsive pain is

known as “opioid rotation,” which is defined as a switch from one opioid to another in an effort to
provide better outcomes. The rationale for this strategy is based on pharmacologic and clinical
observations that suggest that a change in drug is more likely than not to improve the balance
between pain relief and side effects [106].
Equianalgesic opioid dose conversion — Each opioid drug has a different potency,
defined as the dose necessary to produce a given effect. When switching from one opioid to
another, the starting dose of the new drug must be informed by the difference in their relative
potencies. The starting dose of the replacing drug must be close enough to its predicted
equianalgesic dose to prevent the development of withdrawal (if the dose of the new drug is too
low), or unintentional overdose (if it is too high). Equianalgesic dose tables (table 2 and table 3
and table 10) have been developed as a means for comparing potencies among opioids.
Although it is essential to know the approximate equianalgesic dose between drugs when
switching from one to the other, this is only the first step. Although the relative potency estimates
represent the best science after more than 40 years of studies [107], application of the ratios in the
equianalgesic dose table to the clinical setting must be done cautiously because of the following
issues:
● Individual patients may not have the characteristics of those who were included in the relative
potency studies.
● There is very large individual variation in drug metabolism and pharmacodynamics, indicating
that even patients with similar characteristics may have very different responses to different
drugs.
● Tolerance to adverse effects during long-term treatment does not occur to different drugs in
the same way. This “incomplete cross-tolerance” means that a new drug can have
unexpectedly strong effects.
● Because of variations in drug absorption, a dose reduction may be needed when switching
from one route of administration to another (eg, from oral to rectal dosing), even for the same
drug (see 'Rectal' above).
To ensure that opioid rotation is done safely, clinical guidelines have been developed that
incorporate reductions in the calculated equianalgesic dose [108]. These reductions have been
conceptualized as ranges, one automatic and one based on specific patient characteristics, and
clinical judgment must be used to apply them (table 13) [109].
Switching to methadone — A change from any of the pure mu agonist drugs to

methadone is the most challenging aspect of opioid rotation, and the optimal way to switch is
debated. It is clear that the ratios that appear on standard equianalgesic dose tables, which were
derived from studies of patients receiving relatively low doses, may be far from the actual
methadone dose required to achieve a good outcome. In one study, for example, there was no
correlation between high morphine-equivalent doses (MEDs; >1200 mg/day) and the final
methadone dose after stabilization in patients being rotated to methadone [110]. The authors
suggested a fixed maximum methadone dose of no more than 30 mg/day for patients receiving
>1200 mg/day of morphine or MEDs.
This finding supports an approach to conversion that emphasizes safety, including the following
steps:
● Initially, calculate the dose of methadone equal to the total dose of the starting opioid using
the standard equianalgesic dose (table 3).
● Reduce this calculated equianalgesic dose by 75 to 90 percent (table 13) [108]. Do not
exceed a starting dose of 30 mg/day of methadone, even if this reduction yields a dose higher
than 30 mg.
● Methadone can be initiated using a number of strategies. There are two dominant strategies:
the “stop and go” approach, where the current opioid is immediately replaced by methadone,
and the three-day switch, where the dose of the current opioid is reduced step-wise by one-
third each day, and substituted with one-third of the equianalgesic dose of methadone, over
three days [111-116]. There is insufficient evidence to select one strategy preferentially over
another [117]. Switching over a three-day period is probably a preferable strategy as it may
avoid methadone accumulation and toxicity, particularly in patients on high doses of opioids
[10,12,118].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Palliative care" and
"Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain".)
INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.”
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)
● Basics topic (see "Patient education: Managing pain when you have cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Opioids are widely used for treatment of cancer pain because of their safety, multiple routes of
administration, ease of titration, reliability, and effectiveness for all types of pain (ie, somatic,
visceral, and neuropathic). (See 'Introduction' above.)
● The analgesic effect of the drugs typically used to manage cancer pain is a consequence of
agonist action at the mu receptor. Based upon their effects on the mu receptor, opioids are
conventionally divided into pure agonists, agonist-antagonists, and pure antagonists. (See
'Mechanism of action' above.)
● With few exceptions, the management of chronic cancer pain usually involves the long-term
administration of pure mu receptor agonists (table 2 and table 3). However, drugs other than
the pure mu agonists (eg, buprenorphine, and tramadol or tapentadol, mixed-mechanism
centrally acting analgesics) can be used for treatment of cancer-related pain in some
circumstances. (See 'Buprenorphine' above and 'Mixed-mechanism drugs: Tramadol and
tapentadol' above.)
● Mixed agonist-antagonist drugs other than buprenorphine (eg, butorphanol, pentazocine) are
generally not used for cancer pain management. (See 'Mixed agonist-antagonist drugs'
above.)
Choice of initial opioid agonist
● The oral and transdermal routes are preferred for chronic treatment of cancer pain. (See
'Selecting the route of administration' above.)
● Short-acting pure mu receptor agonists such as morphine, oxycodone, hydromorphone, or

oxymorphone are the preferred agents for moderate to severe cancer pain in the patient who
is opioid naïve. There is no evidence to support superior efficacy or tolerability of any agent
over another. (See 'Pure mu agonists commonly used for cancer pain' above.)
Because of genetic variation in metabolism of codeine and an inability to predict drug effects,
we suggest not using codeine in this setting (Grade 2B). (See 'Pure mu agonists rarely used
for cancer pain' above.)
We also suggest not using meperidine because of toxicity concerns (Grade 2B). (See
'Meperidine' above.)
For the opioid-naïve patient, a combination product containing short-acting hydrocodone or

short-acting oxycodone plus acetaminophen is commonly selected. Another option is
buprenorphine in a transdermal formulation, or a mixed-mechanism drug such as tramadol or
tapentadol. Some clinicians use a single entity pure mu agonist like morphine or
hydromorphone or fentanyl, as long as the dose is very low.
● Hydromorphone may be preferred for patients with renal insufficiency. A concentrated solution
of hydromorphone is useful for subcutaneous or intravenous administration if relatively high
doses are needed. If hydromorphone is poorly tolerated in a patient with renal insufficiency,
the preferred alternative may be fentanyl. (See 'Oxycodone, hydrocodone, hydromorphone,
and oxymorphone' above and 'Use in renal failure' above.)
Titration and switch to a long-acting formulation
● Following selection of a starting opioid dose, adjustment is almost always required.

Continuous or frequently recurrent pain is most effectively managed with a fixed schedule,
“around-the-clock” opioid regimen. Although the absolute dose of the opioid is
inconsequential as long as the balance between analgesia and side effects remains
acceptable for the patient, the need to titrate to relatively high doses should be accompanied
by careful reassessment of the pain and drug effects. (See 'Dose titration' above.)
● If a patient is given a short-acting opioid and is needing several doses per day (or if a bedtime
dose does not permit uninterrupted sleep through the night), a switch to a long-acting
modified -release formulation can improve convenience and adherence.
● Morphine has the longest history of use for the treatment of cancer pain and is usually
considered the standard for comparison across opioid drug classes. Any of the single entity
drugs can be selected (table 2 and table 3), and there is no evidence to suggest superior
efficacy or tolerability for any one agent over another. However:
• We suggest transdermal fentanyl over an orally administered opioid in the setting of poor
gastrointestinal tract absorption or dysphagia, and for patients in whom constipation has
been or is expected to be difficult to manage (Grade 2B). (See 'Selecting the opioid'
above and 'Selecting the route of administration' above.)
• For patients with renal insufficiency, we suggest hydromorphone or fentanyl rather than
morphine or oxycodone (Grade 2C). (See 'Use in renal failure' above.)
• Given the challenges inherent in the safe prescribing of methadone, this drug is best
considered second-line, to be tried only in the event that trials of one or more of the other
modified release agents fail to provide an adequate balance between analgesia and side
effects; if the clinician is not clear about the procedures that should be followed to ensure
the safe use of methadone (starting dose, monitoring, timing of dose escalation, etc), it is
best to seek the help of a consultant before starting this therapy. (See 'Methadone'
above.)
Management of breakthrough pain
● Patients who have breakthrough pain should be offered a short-acting supplemental opioid on
an as needed basis in conjunction with a fixed scheduled long-acting drug. The rescue drug
may be a single entity oral formulation, such as immediate release morphine, oxycodone,
hydromorphone, or oxymorphone, or one of the combination products (eg, acetaminophen
plus oxycodone). A typical dose chosen for rescue is 5 to 15 percent of the basal daily
requirement of opioid. (See 'Management of breakthrough pain' above.)
● Breakthrough pain may also be targeted with one of the newer rapid-onset, transmucosal
fentanyl formulations, which are specifically indicated for cancer-related breakthrough pain.
Due to cost and limited experience, the transmucosal drugs are generally considered only
after a patient has demonstrated a poor response to an oral rescue dose. Patients with very-
rapid-onset pain might also be considered for an early trial. Given the lack of comparative
data, there are no recommendations about which of the many formulations might be
preferable. However, if this approach is chosen, the initial rescue dose should be one of the
lowest commercially available doses and not based upon the basal daily opioid requirement.
Regardless of the formulation, the rescue dose should be titrated to yield optimal benefit for
breakthrough pain.
● For patients with severe pain, rapid titration of the opioid dose may be achieved using
intravenous dosing at short intervals. A technique for accomplishing this involves the use of a
patient-controlled analgesia (PCA) pump to administer a continuous infusion of opioid by
either the intravenous or subcutaneous route, plus intermittent bolus “rescue doses.” The
intravenous route has the fastest onset of action. (See 'Subcutaneous and intravenous
administration' above.)
Management of pain that is poorly responsive to opioids
● Several options are available for patients who develop treatment-limiting side effects during
opioid dose titration (table 12).
● One approach, opioid rotation, may improve the balance between pain relief and side effects.
When switching between opioids, equianalgesic dose tables (table 2 and table 3 and table 10)
have been developed as a means for comparing potencies between opioids. However,
application of the ratios in the equianalgesic dose table to the clinical setting is limited by
incomplete cross-tolerance and other factors. Clinical guidelines have been developed that
incorporate reductions in the calculated equianalgesic dose based upon specific patient
characteristics; clinical judgment must be used to apply them (table 13). (See 'Equianalgesic
opioid dose conversion' above.)
Conversion to methadone requires special care given the uncertainty as to the appropriate
ratio to use in conversion from another pure mu agonist to methadone. Initially, we suggest
that the calculated equianalgesic dose (table 3) be reduced by 75 to 90 percent (table 13)
[108]. Regardless of the oral morphine equivalent dose, we would not initiate methadone at a
dose higher than 30 mg/day. (See 'Switching to methadone' above.)
● Another approach that could be considered in patients who have specific types of pain for
which opioid therapy alone is frequently ineffective (eg, neuropathic pain) is the use of
adjuvant analgesics. (See "Cancer pain management: Adjuvant analgesics (coanalgesics)",
section on 'Neuropathic pain'.)
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Topic 2814 Version 72.0
GRAPHICS
Classification of opioids for pain management
Opioid
Medications Notes about therapy
type
Pure agonists Codeine Mainstay of therapy for moderate to severe cancer pain.
Hydrocodone No clinically relevant ceiling effect for analgesia; as dose is raised, analgesic
effects increase until analgesia is achieved or dose-limiting side effects
Dihydrocodeine
supervene.
Morphine Meperidine and propoxyphene are not preferred due to potential effects of toxic
Hydromorphone metabolites.
Fentanyl Methadone must be used with caution; only clinicians who are knowledgeable
about the risks posed by long and variable half-life, unpredictable potency, and
Oxycodone potential for QTc prolongation should use this drug without guidance.
Oxymorphone
Levorphanol
Methadone
Meperidine
Mixed agonist- Buprenorphine Agonist-antagonists include mu receptor agonists with lower intrinsic efficacy
antagonists (partial agonists) and drugs that have agonist effects at one opioid receptor
and antagonist effects at another (mixed agonist-antagonists).
Butorphanol
Most were developed to be less attractive to individuals with the disease of
addiction; this characteristic does not rationalize widespread use for cancer
pain.
Dezocine
All have the potential to induce acute abstinence in patients with physical
dependency on agonist opioids.
Nalbuphine Most of the mixed agonist-antagonists have a ceiling effect for analgesia.
However, buprenorphine does not have a ceiling effect. It is available as a
transdermal patch and in a buccal formulation and may be of use in relatively
Pentazocine
opioid-naïve cancer patients. Some mixed agonists-antagonists (pentazocine
and butorphanol) have a high risk of psychotomimetic side effects.
Mixed- Tramadol Centrally acting analgesics that have agonist actions at the mu receptor and
mechanism block reuptake of monoamines.
drugs Tapentadol
Graphic 69457 Version 7.0
Commonly used, oral and transdermal, long-acting pure mu-opioid agonists for
chronic pain in adults (refer to notes)
Sample
Duration
Brand initial
Serum of
name dose in
Drug half-life analgesic Comments
(United opioid-
(hours) effect
States) tolerant
(hours)
adults
Oral, long-acting preparations
Hydrocodone Hysingla ER 20 mg 7 to 9 24 May interact with drugs that alter

orally CYP3A4 and CYP2D6 metabolism
every 24 Converted to active metabolite
hours by CYP2D6, which is subject to
Zohydro ER 10 mg 13 ≤12 in polymorphisms; individual effects
orally patients with vary
every 12 non-cancer Hysingla ER and Zohydro ER
hours back pain have abuse-deterrent* properties
Hydromorphone Exalgo 8 mg orally 11 24 Use reduced dose in renal and/or

every 24 hepatic impairment
hours Exalgo has abuse-deterrent*
Hydromorph 3 mg orally Not ≥12 properties
Contin every 12 specified
(available in hours
Canada)
Morphine MS Contin, 15 mg Not 8 to 12 Active metabolites are dependent

Oramorph orally specified on kidney function for clearance;
SR every 12 avoid or use reduced dose
hours frequency in organ dysfunction
Kadian 30 mg 11 to 13 12 to 24 Accumulation of metabolite may
orally daily contribute to hyperalgesia or
in 1 or 2 other neurotoxicity
divided Arymo ER has abuse-deterrent*
doses properties
Arymo ER 15 mg Not 8 to 12
orally specified
every 8 or
12 hours
Oxycodone OxyContin, 10 mg 4.5 8 to 12 OxyContin and Oxaydo have

Oxaydo orally abuse-deterrent* properties
every 12
hours
Xtampza ER 9 mg orally 5.6 ≤12 Xtampza ER has abuse-

every 12 deterrent* properties
hours
Oxymorphone Generic only 5 mg orally 9 to 11 12 Take on empty stomach

every 12 Opana ER brand, an abuse-
hours deterrent formulation, was
withdrawn from the United States
market in mid-2017 due to
concerns related to IV injection
abuse, including reports of
thrombotic microangiopathy;
generic extended-
release preparations of
oxymorphone remain available
Transdermal
Fentanyl Duragesic 12 or 25 17 48 to 72 Onset of analgesic effect is

mcg per following Some delayed 12 to 24 hours after
hour, patch patch analgesic initial application
applied removal effect may Approximate dose conversions
every 72 persist for for fentanyl transdermal and
hours up to 12 commonly used oral opioids are
hours provided as a separate table in
following UpToDate
patch
removal
NOTES:
The total daily dose requirement for a long-acting opioid formulation should be established first with the use of
an appropriate immediate-release opioid analgesic. Details for initiating and adjustment of dose vary by each
agent. Refer to UpToDate reviews on chronic non-cancer and cancer pain management with opioids and
individual drug monographs (ie, Lexicomp) for detailed information on individual agents.
Opioids have similar equianalgesic potency whether administered as an immediate-release form (ie, smaller,
more frequently divided doses) or an extended-release preparation. To convert from an oral immediate-release
to an extended-release preparation of the same opioid, use the sum of the doses of the immediate-release
form administered during the usual interval of the extended-release form. As an example, morphine sulfate
immediate-release 30 mg orally every 4 hours (total of 180 mg per day) may be converted to morphine sulfate
extended-release 60 mg orally every 8 hours (total of 180 mg per day).
Approximate equianalgesic dose equivalents and information on oral immediate-release and parenteral pure
mu-opioid agonists that are commonly used in management of chronic non-cancer and cancer-related pain are
provided as separate tables within UpToDate.
CYP3A4: cytochrome P450 3A4; CYP2D6: cytochrome P450 2D6; IV: intravenous; mcg: microgram.
* Abuse-deterrent formulations have 1 or more properties that make intentional manipulation of the dose form more
difficult (eg, resistant to crushing and dissolution) or less likely to produce an opioid effect (eg, altered to minimize
absorption through nasal mucosa). No oral opioid formulation prevents ingestion of an excessive dose.
Courtesy of Kathleen Broglio, DNP, MN, ANP-BC, ACHPN and Russell K Portenoy, MD.
Additional data from:
1. National Comprehensive Cancer Network. Adult Cancer Pain, Version 2.2016.
2. Lexicomp Online. Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.
Commonly used, oral, immediate-release and parenteral pure mu-opioid agonists

for chronic pain: Adult dosing and approximate equivalence (refer to notes)
Drug Sample
Approximate initial Serum Duration
(United
equivalent dose half-life of effect Comments
States brand
doses* (opioid (hours) (hours)
name)
naïve) ¶
Oral immediate-release preparations
Hydromorphone 7.5 mg 2 to 4 mg 2 to 3 3 to 6 High potency

(Dilaudid) orally Use reduced dose in renal
every 3 to and/or hepatic impairment
4 hours
Methadone 20 mg Δ 2.5 to 10 12 to 150 3 to 4 Due to challenges inherent in

(Dolophine, mg orally initially; safe prescribing of
Methadose) every 4 to increases methadone, not a first-line
8 hours after analgesic choice
repeated Can be used as a long-acting
use opioid due to its prolonged
half-life (0.5 to 7 days)
Guidelines must be followed
to reduce risk of
unintentional overdose; refer
to text Δ
Morphine 30 mg 15 to 30 2 to 3 3 to 6 Active metabolites are

mg orally dependent on kidney
every 4 function for clearance; avoid
hours or use reduced dose
frequency in organ
dysfunction
Accumulation of metabolite
may contribute to
hyperalgesia or other
neurotoxicity
Oxycodone 20 mg 5 to 15 mg 2 to 3 3 to 6 Available as a single entity or

(Oxy-IR, orally combined with
Roxicodone) every 4 to acetaminophen, aspirin, or
6 hours ibuprofen; dose limits apply
to combinations
Oxymorphone 10 to 15 mg 5 to 10 mg 7 to 9 3 to 6 Take on empty stomach

(Opana) orally
every 4 to
6 hours
Parenteral preparations
Fentanyl 0.1 mg (100 25 to 50 7 to 12 0.5 to 1 Duration of effect increases

(Sublimaze) mcg) mcg IV or (IV) after repeated use
SQ every 1 1 to 2 (SQ) Can also be administered as
to 2 hours a continuous IV or SQ
infusion
Hydromorphone 1.5 mg IV/SQ 0.3 to 1 2 to 3 3 to 4 High potency (small volume)

(Dilaudid) mg IV useful for SQ administration
every 2 to Can also be administered as
4 hours a continuous IV or SQ
0.3 to 1 infusion
mg SQ
every 3 to
4 hours
Methadone 10 mg IV/SQ Δ 1.25 to 5 12 to 150 3 to 4 Duration of effect increases

mg IV/SQ after repeated use
every 4 to Refer to comments above
8 hours and in text regarding safe
use of methadone Δ
Morphine 10 mg IV/SQ 2 to 5 mg 2 to 3 3 to 4 Can also be administered as

(Infumorph, IV every 2 a continuous IV or SQ
others) to 4 hours infusion
2 to 10 mg Active metabolites are
SQ every 3 dependent on kidney
to 4 hours function for clearance; avoid
or use reduced dose
frequency in organ
dysfunction
Accumulation of metabolites
may contribute to
hyperalgesia or other
neurotoxicity
Oxymorphone 1 mg IV/SQ 0.5 mg IV 7 to 9 3 to 6

(Opana) every 4 to
6 hours
0.5 to 1.5
mg SQ
every 4 to
6 hours
NOTES:
Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. For a review of
multiple factors that must be considered for safely individualizing conversion of opioid analgesia, refer to
UpToDate reviews of cancer pain management with opioids.
Opioids have similar equianalgesic potency whether administered as an immediate-release form (ie, smaller,
more frequently divided doses) or an extended-release preparation. To convert from oral immediate-release to
an extended-release preparation of the same opioid, use the sum of doses of immediate-release administered
during the usual interval of the extended-release form. As an example, morphine sulfate immediate-release 30
mg orally every four hours (total of 180 mg per day) may be converted to morphine sulfate extended-release
60 mg orally every eight hours (total of 180 mg per day).
For information about extended-release and long-acting preparations, and fentanyl transmucosal preparations
for breakthrough pain, refer to the separately available table within UpToDate and the individual drug
monographs.
mcg: micrograms; IV: intravenous; SQ: subcutaneous.

* When switching to a new opioid, the calculated dose of the new opioid should be reduced by 25 to 50% (75 to 90% for
methadone ¶) to adjust for lack of complete mu receptor cross-tolerance. For a review of multiple factors that must be
considered for safely individualizing conversion of opioid analgesia, refer to UpToDate topic on cancer pain management
with opioids: Optimizing analgesia.
¶ Dose reduction of approximately 50% required for older or debilitated adults, or patients with low cardiac output or
respiratory compromise.
Δ When switching to methadone, the calculated equianalgesic methadone dose should be reduced by 75 to 90% and
initiated at no more than 30 mg orally per day (in divided doses), regardless of the previous opioid dose. Guidelines for
safe dose adjustment must be followed to avoid unintentional overdose. Refer to UpToDate topic on cancer pain
management with opioids: Optimizing analgesia, section on methadone.
World Health Organization (WHO) analgesic ladder
NSAID: nonsteroidal antiinflammatory drug.
Some reported causes and potentiators of the long QT syndrome*
Congenital Acquired (continued)

Jervell and Lange-Nielsen syndrome (including Antihistamines
"channelopathies")
Astemizole §, bilastine ¶, hydroxyzine,
Romano-Ward syndrome terfenadine §
Idiopathic Antineoplastic drugs ◊
Acquired High risk: Arsenic trioxide, ivosidenib,

lenvatinib, vandetanib
Metabolic disorders
Moderate risk: Ceritinib, crizotinib, dasatinib,
Hypokalemia encorafenib, gilteritinib, inotuzumab
ozogamicin, midostaurin, nilotinib, osimertinib,
Hypomagnesemia
ribociclib, toremifene, vemurafenib
Hypocalcemia
Analgesic, anesthetic, and sedative drugs
Starvation
Anesthetic/sedative: Chloral hydrate, propofol
Anorexia nervosa
Opioids: Buprenorphine ¥, hydrocodone,
Liquid protein diets loperamide ‡ (in overdose), methadone
Hypothyroidism Bronchodilators (beta-2 agonists)
Bradyarrhythmias Arformoterol, albuterol, formoterol, levalbuterol,
Sinus node dysfunction indacaterol, olodaterol, salmeterol, terbutaline,
vilanterol
AV block: Second or third degree
Diuretics
Androgen deprivation therapy (GnRH
agonist/antagonist therapy or bilateral surgical Via electrolyte changes (especially hypokalemia
orchiectomy) or hypomagnesemia)
Antiarrhythmic drugs Gastrointestinal drugs ◊
Quinidine, procainamide, disopyramide Antidiarrheal: Loperamide ‡ (in overdose)
Flecainide, pilsicainide ¶, propafenone Antiemetics:

Moderate risk: Droperidol, ondansetron (risk
Amiodarone Δ, dronedarone, vernakalant ¶
with IV use greater than oral)
Sotalol Low to moderate risk: Granisetron,
Dofetilide, ibutilide dolasetron, hydroxyzine, tropisetron ¶
Antianginal drugs Promotility:

High risk: Cisapride (restricted availability)
Ranolazine, ivabradine ¶
Moderate risk: Domperidone ¶
Anticholinergic drugs (antimuscarinics)
Low to moderate risk (rare reports):
Solifenacin, tolterodine Metoclopramide
Anti-infective drugs ◊ Proton pump inhibitors: Chronic use leading to

Antimalarial: hypomagnesemia (rare)
High risk: Delamanid ¶, quinidine, quinine Neurologic drugs

Moderate risk: Chloroquine, halofantrine,
Apomorphine, deutetrabenazine, donepezil,
piperaquine
ezogabine, fingolimod, pimavanserin,
Antituberculous: tetrabenazine
High risk: Bedaquiline Psychotropic drugs
Azole antifungals: Antipsychotics: ◊

Moderate risk: Fluconazole, voriconazole High risk: Chlorpromazine, IV haloperidol,
Low to moderate risk: Itraconazole ziprasidone
Moderate risk: Amisulpride ¶, clozapine,
Clofazimine (moderate risk)
flupentixol ¶, haloperidol (oral), olanzapine,
Fluoroquinolones (systemic): quetiapine, risperidone, thioridazine
Moderate risk: Gemifloxacin ¶, levofloxacin, Low to moderate risk: Asenapine,
moxifloxacin, sparfloxacin ¶ iloperidone, paliperidone, pimavanserin
Low to moderate risk: Ciprofloxacin,
Tricyclic and tetracyclic antidepressants (TCAs;
norfloxacin, ofloxacin
†
Foscarnet (low to moderate risk) including doxepin) †
HIV antiretrovirals: Selective serotonin reuptake inhibitors (lower risk

Moderate risk: Saquinavir than TCAs): Citalopram, escitalopram, fluoxetine
Low to moderate risk: Efavirenz, lopinavir- (less than citalopram)
ritonavir, rilpivirine Others:
Macrolide antibiotics: Atomoxetine, trazodone, valbenazine
Moderate risk: Azithromycin, erythromycin, Vasodilator drugs

clarithromycin
Bepridil §, cilostazol
Low to moderate risk: Roxithromycin,
telithromycin Other drugs and herbs
Pentamidine (IV), moderate risk Miscellaneous: Anagrelide, alfuzosin, cocaine,

eliglustat, gadobenate dimeglumine, lofexidine,
Pentavalent antimonials mifepristone, papaverine (intracoronary),
(antiparasitic/antiprotozoal): pasireotide, probucol §, terlipressin ¶
Moderate risk: Meglumine antimoniate,
Herbs: Cinchona (contains quinine), licorice
sodium stibogluconate
extract (glycyrrhizin) in overuse leading to
Telavancin (low to moderate risk) electrolyte changes
Other factors
Myocardial ischemia or infarction, especially with

prominent T-wave inversions
Intracranial disease
HIV infection
Hypothermia
Toxic exposure: Organophosphate insecticides
This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with
either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients, but
may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A
more complete list of such drugs is available at the Credible Meds website.
AV: atrioventricular; IV: intravenous.

* The list of medications and other factors capable of prolonging the QTc represents an evolving area of clinical research.
In some cases of long QTc, two or more factors may be involved.
¶ Not available in the United States.
Δ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes (TdP);
refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome.
◊ Classifications based upon US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation
and Proarrhythic Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and
Drug Administration, June 2017 (revision 2) available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf.
The use of other classification criteria may lead to some agents being classified differently by other sources.
§ Removed from market in most countries due to adverse cardiovascular effects.
¥ Although product labeling for buprenorphine analgesics warn of QTc prolongation at doses exceeding those
recommended, data for buprenorphine in usual doses for treatment of opioid use disorder are reassuring, and it appears
to be a suitable alternative for patients with significant QTc prolongation due to methadone. Refer to the UpToDate topic
reviews of opioid intoxication and opioid use disorder for detail.
‡ Over-the-counter; available without a prescription.
† Several of the cyclic antidepressants have not been adequately tested for QTc prolongation risk.
Data from:
1. Nielsen J, Graff C, Kanters J, et al. Assessing QT interval prolongation and its associated risks with antipsychotics.
CNS Drugs 2011; 25:473.
2. Li E, Esterly J, Pohl S, et al. Drug-induced QT interval prolongation: Considerations for clinicians. Pharmacotherapy
2010; 30:684.
3. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at
http://crediblemeds.org/.
4. Lexicomp Online. Copyright ©1978-2019 Lexicomp, Inc. All Rights Reserved.
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate Strong inducers Moderate inducers

Atazanavir inhibitors Apalutamide Bexarotene
Clarithromycin Amiodarone* Carbamazepine Bosentan
Cobicistat and Aprepitant Enzalutamide Dabrafenib

cobicistat-containing Ceritinib Fosphenytoin Dexamethasone ¶
coformulations
Cimetidine* Lumacaftor Efavirenz
Darunavir
Conivaptan Mitotane Eslicarbazepine
Idelalisib
Crizotinib Phenobarbital Etravirine
Indinavir
Cyclosporine* Phenytoin Lorlatinib
Itraconazole
Diltiazem Primidone Modafinil
Ketoconazole
Duvelisib Rifampin (rifampicin) Nafcillin
Lopinavir
Dronedarone Rifabutin
Mifepristone
Erythromycin Rifapentine
Nefazodone
Fluconazole St. John's wort
Nelfinavir
Fosamprenavir
Ombitasvir-
Fosaprepitant*
paritaprevir-ritonavir
Grapefruit juice
Ombitasvir-
paritaprevir-ritonavir Imatinib
plus dasabuvir
Isavuconazole
Posaconazole (isavuconazonium
sulfate)
Ritonavir and ritonavir-
containing Letermovir
coformulations
Netupitant
Saquinavir
Nilotinib
Telithromycin
Ribociclib
Voriconazole
Schisandra
Verapamil
For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum
concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for
elimination or activation.
These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may
use a different classification system resulting in some agents being classified differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing
of administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant
interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on
CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked
using a drug interaction program such as Lexicomp interactions included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.
References:
1. US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical
implications; Guidance for industry (October 24, 2017) available at: https://www.fda.gov/media/82734/download.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: FDA.gov website.
Schedules of controlled substances in the United States*
Medical Potential for

Schedule Examples Prescription
use? abuse/dependence
I Heroin, marijuana, LSD ¶ No Δ High Not applicable
II Narcotics: Yes High Require a

written
Codeine
prescription by a
Fentanyl
licensed
Hydrocodone and hydrocodone
combinations (eg, with
practitioner.
acetaminophen) Refilling of
Hydromorphone individual
Morphine prescriptions is
Methadone prohibited.
Oxycodone and oxycodone
combinations (eg, with
acetaminophen)
Tapentadol
Stimulants:
Amphetamine
Methamphetamine
Methylphenidate
Other:
Cocaine
Pentobarbital, secobarbital
III Narcotics: Yes Less than with Schedule I A prescription

and II drugs for a drug in
Buprenorphine
Schedules III
Combination products with <90 mg
codeine/unit (eg, acetaminophen with
through V must
codeine) be issued by a
licensed
Non-narcotics:
practitioner and
Dronabinol may be
Ketamine communicated
orally, in
IV Narcotics: Yes Less than with Schedule
writing, or by
III drugs
Tramadol and combinations (eg, with facsimile to the
acetaminophen) pharmacist;
Others: may be refilled
up to five times
Alprazolam
Diazepam
Clonazepam
Lorazepam
Midazolam
V Preparations containing limited Yes Lower than with Schedule

quantities of certain narcotic and IV drugs
stimulant drugs used for antitussive,
antidiarrheal, and analgesic purposes
(eg, cough preparation with <200 mg
codeine/100 mL [eg, Robitussin AC])
* Drugs and other substances that are considered controlled substances under the Controlled Substances Act are divided
into five schedules based upon whether they have a currently accepted medical use in the United States and their relative
abuse potential and likelihood of causing dependence when abused.
¶ Lysergic acid diethylamide
Δ Marijuana is classified as a schedule 1 controlled substance under federal law. Several states have made marijuana legal
for medical and/or recreational use under state law. Marijuana's legal status is reviewed in greater detail in the UpToDate
content on the epidemiology, comorbidity, health consequences, and medico-legal status of cannabis use and cannabis
use disorder.
United States Department of Justice; Drug Enforcement Administration website

http://www.deadiversion.usdoj.gov/schedules/#list.
Dosing and selected characteristics of analgesic drugs for treatment of persistent

pain in older adults
Suggested
Drug initial dose* Selected characteristics relevant to older adults
and titration
Acetaminophen 325 to 500 mg orally Effective analgesic that may decrease opioid requirements; often
(paracetamol) every 4 hours or 500 used in combination with tramadol
to 1000 mg every 6 Clearance is reduced with aging
to 8 hours Maximum 2 g per day suggested for older adults who are frail,
(maximum 3 g per aged ≥80, with significant organ dysfunction, or at risk for
day) hepatotoxicity (eg, regular alcohol use or malnourished)
Interacts with warfarin (prolongs INR) and CYP450-inducing
drugs (increased risk of hepatic inflammation)
Warn patients concerning acetaminophen content in combination
prescription analgesics (eg, oxycodone-acetaminophen) and OTC
preparations
For short-term or one-time use, a total dose of up to 4 g per day
may be considered in selected older adults under medical
supervision (eg, nursing facility)
Opioid analgesics Δ ◊: Older adults are more susceptible to opioid-induced adverse effects, including respiratory
depression, hypotension, delirium, constipation, excessive sedation, and drug accumulation. Low doses should be
used initially and titrated gradually to decrease risk of accumulation and overdose. The initial dose should be
decreased by 25% for a 60-year-old patient and by 50% for an 80-year-old patient, from the initial dose that a 40-
year-old would receive, but administered at the same intervals.
Tramadol
Immediate Start with 25 mg Partial mu-opioid agonist with norepinephrine/serotonin

release § orally once daily reuptake; associated with analgesic dose-ceiling effect, but may
May increase daily be less likely to cause physical dependence
dose by 25 to 50 mg Approximately one-tenth as potent as morphine; wide inter-
after 3 to 7 days; individual variation in response
give in 3 or 4 divided Metabolized by CYP2D6 (polymorphic) to active metabolites
doses May cause nausea and dizziness; slowly titrate to improve
Age ≤75 years: tolerability in older adults
Maximum 400 mg Constipation and sedation less frequent than with strong opioids
daily Renally cleared; dose adjust for renal impairment (CrCl <30
Age >75 years: mL/min)
Maximum 300 mg Can interact with serotoninergic medications (eg, antidepressants
daily and ondansetron)
Renal impairment Avoid use in older adults at risk for seizures

(CrCl <30 mL/min):
Maximum 200 mg
daily irrespective of
age
Extended Start with 100 mg
release orally once daily
May increase daily
dose by 100 mg
after 5 or more days
(maximum 300 mg
daily)
Avoid use in renal
impairment (CrCl
<30 mL/min)
Oxycodone
Immediate Start with 2.5 to 5 Metabolized by CYP2D6 (polymorphic) and CYP3A4 to active
release § mg orally every 4 metabolites
hours as needed Blood levels increased by approximately 50% in older adults with
After 3 to 7 days, renal insufficiency (CrCl <60 mL/min); reduce dose and titrate
determine 24-hour gradually
dose requirement Some opioid-tolerant patients may require every-8-hour dosing
and convert to of extended-release forms for effective analgesia; a 12- to 24-
extended release hour interval is appropriate for most older adults
Extended Divide 24-hour dose

release requirement for
oxycodone
immediate release
in 2 doses
Morphine
Immediate Start with 2.5 to 10 In patients with renal impairment, clearance of active and
release mg orally every 4 potentially neurotoxic metabolites is decreased
hours as needed (an Hydromorphone or fentanyl may be a better choice for older
oral solution is adults with renal impairment (CrCl <60 mL/min)
available for initial For extended-release forms, some patients may require every-8-
low doses; lowest hour dosing for effective analgesia; a 12- to 24-hour dosing
tablet strength interval is appropriate for most older adults
available in the
United States is 15
mg)
After 3 to 7 days,
determine 24-hour
dose requirement
and convert to
extended release
release Δ requirement for
immediate-release
morphine in 1, 2,
or 3 doses
(depending on type
of preparation)
Hydromorphone
Immediate Start with 2 mg Metabolism to apparently inactive metabolites is an advantage

release orally every 4 hours over morphine in older adults with renal or hepatic insufficiency
as needed Accumulation of a neurotoxic (excitatory) metabolite may
After 3 to 7 days, become a concern in older adults with severe renal insufficiency
determine 24-hour or ESRD
dose requirement
and covert to
extended release
release Δ requirement for
immediate-release
hydromorphone in 1
or 2 doses
(depending on type
of preparation)
Transdermal Determine 24-hour Metabolized by CYP3A4 to inactive (nontoxic) metabolites and

fentanyl Δ dose requirement useful in patients with renal and/or hepatic dysfunction
using an immediate- Full effect following application of first patch is delayed by 18 to
release oral opioid; 24 hours
after 3 to 7 days,
Steady state levels may not be reached in older adults until patch
convert to an
is used for 6 to 9 days
equianalgesic dose
Avoid in opioid-naïve patients
of transdermal
fentanyl (refer to Some opioid-tolerant patients may require a 48-hour dosing
Lexicomp drug interval for effective analgesia; a 72-hour dosing interval is
appropriate for most older adults
monograph for initial

conversion)
Or start with 12
mcg/hour patch
every 72 hours; if
ineffective after 1
week, increase to 25
mcg/hour patch
Transdermal 5 mcg/hour patch Partial mu agonist and weak kappa antagonist actions are
buprenorphine Δ every 7 days associated with analgesic dose-ceiling effect but may be less
likely to cause physical dependence than full agonist opioids
Metabolized by CYP3A4 and glucuronidation to active metabolites
Full effect following application of first patch is delayed by up to
72 hours
Limited information on use in renal impairment
Avoid or use with caution in opioid-naïve patients
Precise role in treating older adults with painful conditions not
well established
Methadone Start with 1 mg Consult with a pain specialist prior to prescribing

orally, buccal, or Due to its highly variable half-life and wide inter-individual
subcutaneously pharmacodynamics, methadone has the highest risk of
every 12 to 24 hours accumulation and overdose during initial titration, periodic dose
Increase daily dose adjustment, and conversion from other opioids
by 1 to 2 mg after 7 EKG should be obtained and monitored as methadone use is
or more days associated with QT interval prolongation
Further increases in Due to challenges inherent in safe prescribing of methadone, it is
daily dose of 1 to 2 not a first-line analgesic choice
mg should be made For additional information, refer to the UpToDate topic reviews of
no more frequently treatment of chronic pain and cancer pain management with
than once every 7 opioids
days
Adjuvant analgesics ◊: Includes options for painful polyneuropathies, muscle spasm, and multipurpose analgesics
that may decrease opioid requirements.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Duloxetine Start with 20 to 30 Effective for painful neuropathies, low back pain, fibromyalgia,
mg orally per day and chronic musculoskeletal pain due to osteoarthritis in older
May increase daily adults
dose to 40 to 60 mg Titrate gradually over 2 weeks or more to improve tolerability
after 1 week Avoid in renal impairment (CrCl <30 mL/min) or hepatic
Maximum 60 mg per impairment
day (CrCl ≥30
mL/min)
Venlafaxine Start with 37.5 mg Effective for treatment of various painful polyneuropathies but
(extended orally daily not PHN
release) May increase daily Titrate gradually over 4 weeks or more to improve tolerability
dose by 37.5 mg Dose-related increase in diastolic blood pressure may be seen
after 7 or more
days; then may
increase daily dose
by 37.5 to 75 mg
after 4 or more days
Maximum 225 mg
per day
Milnacipran Start with 12.5 mg Useful for treatment of various painful conditions, including
orally once daily fibromyalgia
(refer to Lexicomp Dose reduction needed for renal impairment
drug monograph for Avoid use in older adults with ESRD or significant hepatic
titration) impairment
Tricyclic antidepressants
Nortriptyline Start with 10 mg Applies to nortriptyline and desipramine:

orally at bedtime Effective for treatment of neuropathies and other painful
May increase daily conditions
dose by 10 mg after Metabolized by CYP2D6 (polymorphic) to active and inactive
7 or more days metabolites
Maximum 50 mg per Dose-related anticholinergic and cardiovascular side effects

night may be poorly tolerated in older adults relative to SNRIs
Titrate gradually over 8 weeks or more to improve tolerability
Desipramine Start with 10 mg
Use low maintenance dose of 25 to 50 mg to decrease risk of
orally at bedtime
accumulation
May increase daily Accumulation toxicity in older adults is less likely with
dose by 10 mg after nortriptyline and desipramine than other tricyclic
7 or more days antidepressants (eg, amitriptyline)
Maximum 50 mg per Low doses used for treatment of painful conditions may be
night insufficient for treatment of depression
Anticonvulsants
Gabapentin Start with 100 mg Applies to gabapentin and pregabalin:

orally at bedtime Effective for treatment of neuropathic and other painful
May increase daily conditions (eg, restless legs syndrome, fibromyalgia)
dose by 100 mg Highly dependent on renal function for clearance
after 7 or more Sedation and dizziness may limit usefulness in frail older adults
days; give in divided Gradual titration over weeks is suggested to improve
doses tolerability and to decrease risk of overdose due to the delayed
Maximum 3600 mg onset of effect
per day (CrCl ≥60 Maximum maintenance dose is determined by renal function;
mL/min) refer to Lexicomp monograph for detail
Pregabalin Start with 25 to 50

mg orally at bedtime
May increase daily
dose by 25 to 50 mg
after 7 or more
days; give in divided
doses
Maximum 300
mg/day (CrCl ≥60
mL/min)
Oral nonsteroidal antiinflammatory drugs (NSAIDs)

Applies to all:
Due to increased side effects in older adults, use should be limited to brief course(s) in selected patients for
painful flare-ups at lowest effective dose
Avoid use of NSAIDs in older adults with renal insufficiency (CrCl <50 mL/min), GI bleeding, platelet
dysfunction, reduced cardiac output, hypovolemic state, hyponatremia, hepatic impairment, or receiving an
anticoagulant
Dose- and age-associated risk of gastropathy; pharmacologic gastroprotection may be indicated even with
COX-2 selective therapy (refer to UpToDate topic on prevention of NSAID-associated gastroduodenal toxicity)
Can cause or worsen renal insufficiency, including age-associated decline in renal function
Traditional NSAIDs (eg, ibuprofen, naproxen) reversibly inhibit platelet functioning and may alter
cardioprotective effects of aspirin
Use with serotonin reuptake inhibitor antidepressants (eg, SSRIs, nortriptyline, venlafaxine) additively
decreases platelet functioning
Naproxen 220 mg twice daily Less cardiovascular toxicity than other nonselective NSAIDs
sodium (equivalent to 200 Naproxen sodium has better absorption and more rapid onset
mg naproxen base than naproxen base
twice daily)
Ibuprofen 200 mg 3 times daily Short half-life may be advantageous in older adults
Avoid combined use with cardioprotective (low-dose) aspirin
therapy
Celecoxib 100 mg daily Relative reduction in GI toxicity compared with nonselective

NSAIDs
No effect on platelet functioning
Patients taking cardioprotective aspirin may still need concurrent
gastroprotection (eg, proton pump inhibitor)
Diflunisal 250 mg 2 or 3 times Applies to nonacetylated salicylates:

daily No effect on platelet functioning at doses shown
Choline 500 to 750 mg 3 Generally tolerated by adults with asthma
magnesium times daily Relatively slow onset
trisalicylate
Salsalate 500 mg 2 or 3 times

daily
Topical therapies: Include topical NSAIDs, capsaicin, and topical lidocaine, which may be useful in combination
with systemic therapies for reducing medication load and side effects for treatment of localized painful conditions;
refer to separate table on topical analgesics.
Intra-articular glucocorticoids: Refer to topic review of initial pharmacologic therapy of osteoarthritis.
INR: international normalized ratio; OTC: over-the-counter (non-prescription) medicines; CrCl: creatinine clearance;
ESRD: end-stage renal disease; EKG: electrocardiogram; PHN: postherpetic neuralgia; GI: gastrointestinal; SSRI:
selective serotonin reuptake inhibitor.
* Lowest starting dose shown should be considered in frail older persons with a history of sensitivity to central nervous
system-active drugs, reduced cardiac output, dehydration, low body weight, or poor oral intake. Doses shown are for oral
administration except where noted.
Δ We suggest establishing dose and effects using an immediate-release opioid preparation prior to prescribing a
sustained-release opioid for opioid-naïve older patients.
◊ In general, dose tapering is recommended prior to discontinuation of anticonvulsants, opioids, and antidepressants.
§ Also available in combination preparations with acetaminophen (paracetamol).
Courtesy of Drs. Marissa Galicia-Castillo and Debra Weiner with additional data from:
1. American Geriatric Society Panel on Pharmacological Management of Persistent Pain in Older Persons.
Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009; 57:1331.
2. Barkin R, Beckerman M, Blum S, et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the
older adult? Drugs Aging 2010; 27:775.
3. van Ojik AL, Jansen PA, Brouwers JR, van Roon EN. Treatment of chronic pain in older people: evidence-based
choice of strong-acting opioids. Drugs Aging 2012; 29:615.
4. Fitzcharles MA, Lussier D, Shir Y. Management of chronic arthritis pain in the elderly. Drugs Aging 2010; 27:471.
5. Drugs for pain. Treat Guidel Med Lett; 2013. 11:31.
Analgesic use in adult patients with advanced chronic liver disease or cirrhosis
Altered response and

Management suggestions
pharmacokinetics
Non-opioid analgesics
Acetaminophen Glutathione tissue stores needed to block Acetaminophen is generally well tolerated
(paracetamol) formation of acetaminophen's toxic in patients with CLD or cirrhosis who do
metabolite (NAPQI) are reduced in not consume alcohol, provided the total
individuals with cirrhosis or malnutrition, daily dose is limited to no more than 2
thereby lowering the dose threshold of g/day.
acetaminophen that can be safely For short-term or one-time use, a
administered each day. maximum total acetaminophen dose of
Active alcohol consumption further up to 4 g/day may be considered in lower
reduces available glutathione stores. risk patients who do not consume alcohol
Half-life of acetaminophen may be and have CLD or early stage
prolonged by up to 2-fold compared with compensated cirrhosis.
healthy patients. Warn patients concerning acetaminophen
content in combination prescription
analgesics (eg, oxycodone-
acetaminophen) and non-prescription
(OTC) preparations.
Avoid use in patients with advanced CLD
or cirrhosis who are actively consuming
alcohol, malnourished, not eating,
receiving multiple medications that
undergo hepatic biotransformations, or
any co-administered medication that is a
potent inducer of hepatic enzymes.
A list of medications that induce hepatic
enzymes is provided in a separate table.
Nonselective An increased risk of GI mucosal bleeding, NSAIDs and aspirin should be avoided in
nonsteroidal variceal hemorrhage, impaired renal patients with advanced CLD or cirrhosis.
antiinflammatory function, and development of diuretic- Low-dose acetaminophen should be used
drugs (NSAIDs) resistant ascites is seen with use of instead of NSAIDs.
including aspirin NSAIDs in patients with cirrhosis with
portal hypertension.
NSAIDs can decrease GFR and impair
renal function in patients with advanced
CLD or cirrhosis.
Most NSAIDs are metabolized by CYP and
highly bound to serum albumin,
increasing drug bioavailability and
potential for toxicity in patients with
advanced CLD or cirrhosis.
Individual NSAIDs (eg, diclofenac) have
been associated with hepatotoxicity in
general population.
Selective COX-2 Available data are inadequate to establish We advise against use of selective COX-2
inhibitors the safety of selective COX-2 inhibitors in inhibitors in patients with advanced CLD
patients with advanced CLD or cirrhosis. or cirrhosis, pending availability of
Refer to UpToDate content for detail. additional safety data.
Excess cardiovascular events have been If used, celecoxib product information
observed with this class of medications suggests a 50% dose reduction for Child-
when used by patients without cirrhosis. Pugh class B cirrhosis.
Opioid analgesics (refer to important note)*
Fentanyl Metabolized by CYP3A4 to inactive Generally a good choice for patients with
(nontoxic) metabolites. CLD or cirrhosis when opiate treatment
is indicated.
Parent drug can accumulate after Useful option in patients with renal failure
repeated dosing or when administered as in setting of cirrhosis.
a continuous infusion due to tissue and No dose adjustment needed for single
protein binding. dose.
Less histamine release than other With repeated dosing, reduce dose and
opiates. frequency by approximately 25 to 50%.
Less hemodynamic disturbance than Initiate transdermal patch at half usual
other opiates. dose.
Hydrocodone, Metabolized to active metabolite by Due to variability of onset and analgesic

oxycodone CYP2D6 and CYP3A4, which may result in efficacy in hepatic insufficiency, fentanyl
a prolonged time to onset, variable or hydromorphone may be better
analgesic efficacy, and risk of tolerated and more safely and predictably
accumulation in patients with advanced adjusted than hydrocodone and
CLD or cirrhosis. oxycodone in patients with advanced CLD
or cirrhosis.
If used, reduce dose and frequency.
Hydromorphone Hepatically metabolized by non-CYP Generally a good choice for patients with
transformations (glucuronidation) to advanced CLD or cirrhosis.
apparently inactive metabolites. Reduce dose and frequency by
Oral bioavailability in advanced CLD or approximately 50%.
cirrhosis seems to be increased relative to Titrate dose gradually to avoid
healthy individuals due to diminished accumulation of active drug.
first-pass extraction, but specific data are Useful option in patients with renal failure
lacking, and wide inter-individual in setting of cirrhosis.
variability is observed.
Small volume for IV preparation and non-
CYP3A4 metabolism may be
advantageous given clinical setting.
Meperidine Altered oral bioavailability and elevated Meperidine and codeine should be
(pethidine), risk of accumulation of intermediates avoided in patients with advanced CLD or
codeine (codeine) or toxic metabolite cirrhosis.
(meperidine).
Meperidine is highly bound to serum
protein.
Unpredictable analgesic efficacy and
increased risk of toxicity in patients with
Morphine Oral bioavailability in advanced CLD or Reduce dose and frequency by

cirrhosis increased up to 100% relative to approximately 50% in advanced CLD or
healthy individuals due to diminished cirrhosis.
first-pass extraction. Wide inter-individual Titrate dose gradually to avoid
variability may be seen. accumulation of active drug.
Hepatically metabolized by non-CYP Avoid in patients with cirrhosis and renal
transformations (glucuronidation). failure.
Half-life can be increased by up to 2-fold.
Accumulation of metabolites with complex
effects (eg, respiratory depression,
analgesic tolerance, neurotoxicity) can
occur in patients with cirrhosis and renal
failure.
Naloxone- Orally administered naloxone, which is Oxycodone-naloxone:

containing opioid included in these combinations to deter Reduce starting dose by one-half to
combinations abuse (ie, crushing, snorting) and two-thirds in mild hepatic impairment.
counteract constipation by a local effect, Use in advanced CLD or cirrhosis is
is systemically absorbed in patients with contraindicated.
moderate to severe hepatic impairment.
Pentazocine-naloxone: Avoid use.
Systemic absorption of naloxone will
reverse analgesic efficacy and can
precipitate opioid withdrawal.
Remifentanil Cleared by nonspecific plasma esterases No adjustment needed.
to inactive metabolites.
Does not accumulate in hepatic or renal
insufficiency.
Prompt reversal of analgesia and sedation
upon discontinuation.
Tramadol Hepatically metabolized to active Avoid use in patients with

metabolite by CYP3A4, CYP2D6, and decompensated cirrhosis.
glucuronidation. Avoid use in patients at risk for seizures.
Unpredictable onset, variable analgesic Based on limited experience, a reduced
efficacy, and risk of accumulation in dose of 25 mg every 8 hours may be
patients with cirrhosis. considered for treatment of pain in
Can interact with serotoninergic patients with advanced CLD or well-
medications, including antidepressants. compensated cirrhosis.
Adjunctive agents for neuropathic pain
Carbamazepine Carbamazepine is a potent inducer of Carbamazepine should be avoided as

hepatic enzymes and has been associated there are safer options for treatment of
with hepatotoxicity and serious allergic neuropathic pain in patients with
reactions in genetically predisposed advanced CLD or cirrhosis.
individuals.
May precipitate rapid decompensation in
patients with cirrhosis.
Gabapentin Not hepatically metabolized or bound to Initiate treatment at 300 mg orally per
plasma proteins. day and gradually titrate dose if needed
Highly dependent on renal function for over weeks due to delayed onset of
clearance of unchanged drug. action and to improve tolerability.
Sedation, ataxia, dizziness, and nausea Maintenance dose is dependent on renal
may limit usefulness in patients with function. For specific adjustment, refer to
advanced CLD or cirrhosis. Lexicomp monograph included with
UpToDate.
According to the product information,
should not be abruptly stopped due to
risk of discontinuation symptoms (eg,
nausea, insomnia, anxiety) and/or
rebound seizures in at-risk patients.
Lidocaine topical Low (3 to 5%) systemic absorption A good choice for local relief of pain in
patch through intact skin. limited areas of intact skin in patients
with advanced CLD or cirrhosis.
No adjustment needed in hepatic
impairment.
Nortriptyline Subject to extensive first-pass Initiate treatment at 10 mg orally each

metabolism and CYP2D6 transformations, night and gradually titrate dose if needed
which include active and inactive over weeks due to delayed onset of
metabolites. action and to improve tolerability.
Accumulation of metabolites in hepatic Use "low" maintenance dose for
impairment is less likely with nortriptyline neuropathic pain (eg, 25 mg to no more
than amitriptyline. than 50 mg daily) to decrease risk of
Dose-related anticholinergic and accumulation.
cardiovascular side effects may be poorly
tolerated in medically ill patients with
Pregabalin Not hepatically metabolized or bound to Initiate treatment at 50 mg orally twice

plasma proteins. per day and gradually titrate dose if
Highly dependent on renal function for needed over weeks due to delayed onset
clearance of unchanged drug. of action.
Sedation and dizziness may limit Maintenance dose is dependent on renal
usefulness in patients with advanced CLD function. For specific adjustment, refer to
or cirrhosis. Lexicomp monograph included with
UpToDate.
According to the product information,

should not be abruptly stopped due to
risk of discontinuation symptoms (eg,
nausea, insomnia, anxiety) and/or
rebound seizures in at-risk patients.
For information about use and adjustment of medications other than analgesics in CLD, refer to separate table in
UpToDate on non-analgesic medications used in adult patients with advanced CLD or cirrhosis.
NAPQI: n-acetyl-p-benzoquinone imine; CLD: chronic liver disease; OTC: over the counter; GI: gastrointestinal; GFR:
glomerular filtration rate; CYP: cytochrome P-450; COX-2: cyclooxygenase 2; IV: intravenous; HE: hepatic
encephalopathy.
* NOTE: All opioids can worsen or precipitate HE and should be used cautiously or avoided in patients with portal
hypertension and preexisting HE.
Prepared with data from:

1. Lewis JH, Stine JG. Review article: Prescribing medications in patients with cirrhosis – a practical guide. Aliment
Pharmacol Ther 2013; 37:1132.
2. Chandok N, Watt KD. Pain management in the cirrhotic patient: The clinical challenge. Mayo Clin Proc 2010;
85(5):451.
Commonly available fentanyl transmucosal preparations for breakthrough pain in

opioid-tolerant adults
Duration of
Fentanyl Starting dose
Brand name Serum half-life analgesic
transmucosal in an opioid-
(United States) (hours) ¶ effect
preparation tolerant adult*
(hours) ¶
Buccal tablet Fentora 100 mcg 13.3 1 to 2
Oral lozenge Actiq 200 mcg 7.6 2
Nasal spray Lazanda 100 mcg 15 to 25 ≥1
Sublingual spray Subsys 100 mcg 5 to 12 ≥1
Sublingual tablet Abstral 100 mcg 11.5 to 25 1
An oral, immediate-release (IR) preparation (eg, oxycodone IR) is generally used for managing brief episodes of
breakthrough pain not attributed to inadequate doses of scheduled long-acting opioids. A transmucosal fentanyl
preparation can provide an alternative to oral IR opioid preparations in patients who may benefit from a more
rapid onset of analgesia, ie, 5 to 15 minutes for transmucosal route compared with 10 to 15 minutes typically for
oral IR opioids.
mcg: microgram.
* Always initiate transmucosal fentanyl preparations at the lowest starting dose for breakthrough pain, even in patients
with high baseline opioid requirements. Data do not support specific transmucosal fentanyl dose equivalents to other
opioids. For additional detail, including recommendations on frequency of repeat dosing, dose titration, and
recommendations on converting between transmucosal forms if necessary, refer to the Lexicomp fentanyl monograph
included in UpToDate.
¶ Serum half-life and duration of effect are dose dependent.
Approximate dose conversions for commonly used opioids (refer to important

note below)
Approximate dose conversions for commonly used opioids (refer to important note
below)
Fentanyl
Hydromorphone (Dilaudid) Morphine Oxycodone
transdermal*
Oral Oral
IV (mg/day) IV (mg/day) Oral (mg/day) Patch (mcg/hour)
(mg/day) (mg/day)
1.25 6.25 8.5 25 15 12
2.5 12.5 17 50 30 25
5 25 33 100 65 50
7.5 37.5 50 150 100 75
10 50 67 200 130 100
12.5 62.5 83 250 165 125
15 75 100 300 200 150
17.5 87.5 117 350 230 175
20 100 133 400 265 200
22.5 112.5 150 450 300 225
25 125 167 500 330 250
27.5 137.5 183 550 360 275
30 150 200 600 400 300
Approximate equianalgesic doses and ratios to determine daily morphine equivalent

dose (MED) for commonly used opioids
Drug Approximate equivalent Approximate Ratio to determine

oral dose equivalent IV or daily MED
subcutaneous dose (morphine:alternate
opioid)
Fentanyl Not available 0.1 mg (100 mcg) 100:1 (parenteral)
Hydrocodone 30 mg Not available 1:1 (oral) ¶
Hydromorphone 7.5 mg 1.5 mg 4:1 (oral); 6.7:1

(parenteral)
Morphine 30 mg 10 mg Reference standard
Oxycodone 20 mg Not available 1.5:1 (oral)
Oxymorphone 10 to 15 mg 1 mg 3:1 to 2:1 (oral); 10:1

(parenteral)
Important note: Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents.
When switching to a new opioid, the initial daily dose for the new opioid determined by using above conversions
should be reduced by 25 to 50% to adjust for lack of complete mu receptor cross-tolerance (except when
switching to methadone, which requires a 75 to >90% reduction; refer to text). For a review of multiple factors
that must be considered for safely individualizing conversion of opioid analgesia, refer to UpToDate topic on cancer
pain management with opioids, optimizing analgesia.
IV: intravenous; mcg: microgram.

* Suggested doses for conversion to transdermal fentanyl from other opioids are less conservative than recommendations
in the United States product labeling. The recommendations in this table are based on guidance available at experienced
centers.
¶ Wide interpatient variability in response.
Differential diagnosis of opioid poorly responsive pain
Pain related to the underlying disease

Cancer progression (eg, new fracture at site of known bone metastases)
New onset of specific etiologies of pain (eg, neuropathic pain, skin ulceration, rectal tenesmus, myalgia) that are
known to be less responsive to systemic opioids or opioid monotherapy
Psychological/spiritual pain related to the experience of an end stage illness (existential pain of impending death)
Opioid pharmacology/technical problems

Opioid tolerance (eg, rapid dose escalation with no analgesic effect)
Dose-limiting opioid toxicity (eg, sedation, delirium, hyperalgesia, nausea)
Poor oral absorption (for oral medications) or skin absorption (eg, transdermal patch adhesive failure)
Pump, needle, or catheter problems (intravenous, subcutaneous, or spinal opioids)
Pain unrelated to the primary disease process

Worsening of a preexisting noncancer pain syndrome (eg, diabetic neuropathy)
New noncancer pain syndrome (eg, dental abscess)
Other psychological problems

Depression, anxiety, somatization, hypochondria, factitious disorders
Dementia and delirium both can effect a patient's report of and experience of pain
Opioid substance use disorders or opioid diversion
Reproduced with permission from: Sacks T, Weissman DE, Arnold R. Opioid Poorly-Responsive Pain. Fast Facts and
Concepts. May 2009; 215. Available at: https://www.mypcnow.org/blank-l1go9. Copyright © 2009 EPERC.
Options when a patient is poorly responsive to an opioid
Approach Options
Try to find a more effective opioid Opioid rotation
Try to open the "therapeutic window" More aggressive side effect management
Try adding a systemic or spinal co-analgesic to reduce Add a systemic NSAID or an adjuvant analgesic, or trial
the opioid requirement of neuraxial (intrathecal, intraspinal) analgesia
Try adding a nonpharmacologic approach to reduce the Consider neural blockade, a neurostimulatory approach,
opioid requirement or a psychological or rehabilitative therapy
NSAID: nonsteroidal anti-inflammatory drug.
Guidelines for opioid rotation [1]
Step 1:
Consider opioid rotation as a strategy to address the scenario of poor opioid responsiveness following dose
titration.
The decision about the drug to which the patient is switched is empirical, based on prior experience of the patient
and physician, availability, cost, and other factors.
When the new drug is selected, calculate the equianalgesic dose from an equianalgesic dose table.
If switching to any opioid other than methadone or fentanyl, identify an "automatic dose reduction window" equal
to a reduction of 25 to 50 percent below the calculated equianalgesic dose.
If switching to methadone, the "automatic dose reduction window" should be a 75 to 90 percent reduction below
the calculated equianalgesic dose. Great caution should be exercised in converting to methadone at doses of 100
mg or greater per day; consider inpatient monitoring, including serial EKG monitoring. Some have recommended
that regardless of the oral morphine equivalent dose, methadone should be initiated at no more than 30 mg per
day [2].
If switching to transdermal fentanyl, do not do an automatic dose reduction and use the calculated equianalgesic
dose included in the FDA-approved manufacturer's labeling for these formulations.
Select a dose closer to the lower boundary (25 percent reduction) or the upper boundary (50 percent reduction)
of the "automatic dose reduction window" on the basis of a clinical judgment that the equianalgesic dose table is
relatively more or less applicable, respectively, to the specific characteristics of the opioid regimen or patient:
Select a dose closer to the upper boundary (50 percent reduction) of the reduction if the patient is receiving a relatively
high dose of the current opioid regimen, is not Caucasian, or is elderly or medically frail.
Select a dose closer to the lower boundary (25 percent reduction) of the reduction if the patient does not have these
characteristics or is undergoing a switch to a different route of systemic drug administration using the same drug.
Step 2:
Before finally selecting the starting dose of the new opioid, perform a second assessment of pain severity and
other medical or psychosocial characteristics to determine whether to apply an additional increase or decrease of
15 to 30 percent to enhance the likelihood that the initial dose will be effective for pain, or conversely, unlikely to
cause withdrawal or opioid-related side effects.
After the initial doses, assess response and titrate the dose of the new opioid regimen to optimize outcomes.
If a supplemental "rescue dose" is used for titration, calculate this at 5 to 15 percent of the total daily opioid dose
and administer at an appropriate interval; an exception are the oral transmucosal fentanyl formulations, which
should be initiated at one of the lower available doses irrespective of the baseline opioid dose.
EKG: electrocardiogram; FDA: Food and Drug Administration.
References:
1. Fine PG, Portenoy RK; Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing
"best practices" for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage 2009; 38:418.
2. Chaham MS, Dodds A ES, Svengsouk JS, Juba KM. Dose ratios between high dose oral morphine or equivalents and
oral methadone. J Palliat Med 2013; 16:947.

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Cancer pain management with opioids: Optimizing

● (See "Assessment of cancer pain".)

OPIOID DRUGS USED IN CANCER PAIN MANAGEMENT

Pure mu agonists commonly used for cancer pain

Metabolite concentration may be idiosyncratically high as a result of unknown but presumed

Oxycodone, hydrocodone, hydromorphone, and oxymorphone — As with morphine,

Short-acting hydrocodone is only available in the United States in combination with

Fentanyl — Fentanyl is a highly lipophilic opioid that may be used parenterally or in

Rapid-onset transmucosal preparations of fentanyl are discussed below. (See 'Management of

Levorphanol — Levorphanol is distinguished by its relatively long half-life (approximately 12 to

Methadone — Methadone is a mu agonist opioid, but it has a unique pharmacology that

● Perhaps more challenging, methadone is marketed in most of the world as a racemate

● Methadone is metabolized by CYP3A4 and CYP2B6 isoenzymes, and to a lesser extent, by

● Similarly, a Cochrane review of 10 studies comparing tramadol with either placebo or an

Mixed agonist-antagonist drugs

Buprenorphine — Buprenorphine is available as a treatment for opioid addiction and as a

Other drugs — Drugs of the mixed agonist-antagonist group (butorphanol, dezocine,

PRACTICAL CONSIDERATIONS IN OPIOID USE

● Meperidine (Demerol) is particularly dangerous, since its active metabolite, normeperidine,

● Morphine is metabolized in part to a potent opioid metabolite, morphine-6-glucuronide, and a

Typically, a short-acting supplemental opioid is offered on an as needed basis for breakthrough

Selecting the route of administration

Transdermal buprenorphine is available in some countries, including the United States. As

Subcutaneous and intravenous administration — Among patients with a progressive illness

transdermal route to be switched, at least temporarily, to continuous intravenous (IV) or

Patients receiving continuous IV or SC infusion may benefit from access to intermittent

Patient-controlled analgesia — A pump with a patient-controlled analgesia (PCA) option

● Two to three days for the modified-release oral formulations.

● Three to six days for the transdermal patch.

A physical examination should be completed, and diagnostic studies ordered, as indicated.

Opioid rotation — A common approach to the management of poorly responsive pain is

Switching to methadone — A change from any of the pure mu agonist drugs to

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Choice of initial opioid agonist

● Short-acting pure mu receptor agonists such as morphine, oxycodone, hydromorphone, or

For the opioid-naïve patient, a combination product containing short-acting hydrocodone or

Titration and switch to a long-acting formulation

● Following selection of a starting opioid dose, adjustment is almost always required.

Management of breakthrough pain

Management of pain that is poorly responsive to opioids

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 2814 Version 72.0

Classification of opioids for pain management

Graphic 69457 Version 7.0

Oral, long-acting preparations

Hydrocodone Hysingla ER 20 mg 7 to 9 24 May interact with drugs that alter

Hydromorphone Exalgo 8 mg orally 11 24 Use reduced dose in renal and/or

Morphine MS Contin, 15 mg Not 8 to 12 Active metabolites are dependent

Oxycodone OxyContin, 10 mg 4.5 8 to 12 OxyContin and Oxaydo have

Xtampza ER 9 mg orally 5.6 ≤12 Xtampza ER has abuse-

Oxymorphone Generic only 5 mg orally 9 to 11 12 Take on empty stomach

Fentanyl Duragesic 12 or 25 17 48 to 72 Onset of analgesic effect is

Graphic 111207 Version 8.0

Commonly used, oral, immediate-release and parenteral pure mu-opioid agonists

Oral immediate-release preparations

Hydromorphone 7.5 mg 2 to 4 mg 2 to 3 3 to 6 High potency

Methadone 20 mg Δ 2.5 to 10 12 to 150 3 to 4 Due to challenges inherent in

Morphine 30 mg 15 to 30 2 to 3 3 to 6 Active metabolites are

Oxycodone 20 mg 5 to 15 mg 2 to 3 3 to 6 Available as a single entity or