VOLUME 32 䡠 NUMBER 16 䡠 JUNE 1 2014

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

Sebastiano Mercadante and Vittorio
Gebbia, La Maddalena Cancer Center,
Palermo; and Giampiero Porzio, Univer-
sity of L’Aquila, L’Aquila, Italy.
Published online ahead of print at
www.jco.org on May 5, 2014.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Sebastiano
Mercadante, MD, Anesthesia and Inten-
sive Care Unit, Pain Relief and Palliative
Care Unit, La Maddalena Cancer
Center, Via S. Lorenzo 312, 90146,
Palermo, Italy; e-mail: terapiadeldolore@
lamaddalenanet.it.
© 2014 by American Society of Clinical
Oncology
0732-183X/14/3216w-1671w/$20.00
New Opioids
Sebastiano Mercadante, Giampiero Porzio, and Vittorio Gebbia
A B S T R A C T
Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is
a lack of evidence to support many aspects of current clinical practice. Therefore, there is a
significant need for more effective treatment options. New opioids have been marketed in the
past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined
mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral
analgesic that possesses a combined mechanism of action: ␮-opioid receptor activation with
norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been
initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local
antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of
naloxone, particularly in a prolonged-release formulation. New delivery systems have been
developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the
upcoming availability of these new drugs and technologies that will add to existing types of opioid
medication, their benefits and liabilities will ultimately need to be determined by the individual
physician and individual patient experiencing pain.
J Clin Oncol 32:1671-1676. © 2014 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2013.51.8662 Despite the skilled use of opioid analgesics,

INTRODUCTION
Opioids are the most potent analgesics available
in clinical practice and remain the cornerstone of
pain management in the cancer population. Not
only can uncontrolled pain have deleterious
physical effects, but when persistent, pain can de-
stroy patients’ autonomy, dignity, and decision-
making capacity.1 Opioid use has been increasing
in recent years. However, many concerns exist
regarding this increased opioid use in noncancer
pain because of a lack of evidence supporting
long-term effectiveness, the misuse of opioids,
and poor data regarding adverse drug events
associated with long-term opioid use, such as en-
docrine dysfunction, immunosuppression, and
opioid-induced hyperalgesia.2
Although opioid use for noncancer pain has
raised many concerns, opioids are the indisputable
cornerstone of pain management in the cancer pop-
ulation, often complemented by numerous other
nonmedical interventions, which are also of para-
mount importance. Indeed, new data released to the
public have painted a picture of unnecessary pain on
a global scale because of a failure to ensure adequate
access to pain-relieving drugs.3 Reasons for this fail-
ure include lack of knowledge regarding opioid use
as well as cultural barriers among health profession-
als regarding the use of opioids and late referral to
palliative care.4
which is crucial to the relief of cancer pain, there is a
lack of evidence to support many aspects of current
clinical practice. A group of experts from the Euro-
pean Association for Palliative Care identified no
significant differences between morphine, oxy-
codone, and hydromorphone administered orally;
recognized transdermal drugs as alternatives to oral
opioids that may be recommended as the preferred
opioids for some patients, such as those who are
unable to swallow; and recommended that meth-
adone be administered only by professionals ex-
perienced in its use.5 These recommendations are
weak, in terms of evidence, given the lack of ap-
propriate studies, confirming the need to find
additional solutions.
The use of opioids is frequently associated with
adverse effects, particularly opioid-induced bowel
dysfunction, which may negatively influence pa-
tients’ quality of life. Unlike many opioid adverse
effects, which tend to disappear over time, constipa-
tion can produce a persisting burden of symptoms
for patients with cancer.
New analgesic options may provide alternative
and more effective treatments. Moreover, in the last
decade, new drug delivery systems have extended
the use of analgesics beyond conventional drug de-
livery routes. Innovative drug delivery systems have
been designed to provide rapid analgesia for the
management of breakthrough pain. The aim of this

© 2014 by American Society of Clinical Oncology 1671

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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
 Mercadante, Porzio, and Gebbia
Table 1. New Available Opioid Formulations in Cancer Pain Management
Approximate Ratio
Opioid to Oral Morphine Mechanism
Hydrocodone 2:1 ␮-receptor agonist
Oxymorphone 1.8:1 ␮-receptor agonist
Tapentadol 1:3.3 Weak ␮-receptor agonist; inhibition Typical opioid adverse effects
noradrenaline reuptake
Oxycodone plus 1.5:1 ␮-receptor agonist; intestinal
naloxone ␮-receptor antagonist
Buprenorphine plus Not available Partial ␮-receptor agonist;
naloxone ␮-receptor antagonist
Rapid-onset opioids Buccal tablet, 100:1; sublingual, ␮-receptor agonist
(fentanyl) 100:1; nasal, 200:1; nasal-
pectin, 100:1
article is to examine the new opioid drugs and combinations de-
veloped in recent decades, emerging drug development strategies,
and new delivery systems to provide opioids through mucosal
routes (Table 1).
NEW OPIOIDS
Hydrocodone
Hydrocodone has been commonly marketed in combination
with different dosages of acetaminophen5; the latter can limit the
number of tablets that can be taken in a 24-hour period. The use of
products containing acetaminophen in high doses over long periods
of time has the potential to cause liver damage. Unlike those drugs,
recent long-acting formulations of hydrocodone do not include acet-
aminophen. In these long-acting preparations, coated and uncoated
beads are combined to produce the desired drug release profile. A
permeable ammonio-methacrylate copolymer coating allows GI fluid
to enter the beads and solubilize the drug, which may then diffuse out
of the beads at a predetermined rate.6 The dosage of extended-release
hydrocodone of 45 or 50 mg per day would result in a morphine
equivalent of 90 or 100 mg per day. A novel abuse deterrent, a
prolonged-release tablet form of hydrocodone for once-daily dosing
has been developed based on the Abuse Deterrent Prolonged Release
Erodible Matrix technology. The formulation consists of an erodible
matrix in which hydrocodone is dispersed. The matrix is partly cov-
ered with a water-impermeable, nonerodible shell, which leaves both
ends of the cylindrical tablet exposed to erosion by GI fluid. A defined
size of the surface erosion area regulates the release of the drug, allow-
ing a controlled, prolonged release of hydrocodone.7
CYP3A4 and CYP2D6 isoenzymes play a major role in the me-
tabolism of hydrocodone. The principal metabolites are norhydro-
codone and hydromorphone. The latter is more potent than
hydrocodone and probably represents the active metabolite of hydro-
codone. As a consequence, patients who are ultrarapid metabolizers
may produce more hydromorphone, whereas poor metabolizers may
experience poor analgesia.8 Drugs that inhibit CYP3A4 activity may
1672 © 2014 by American Society of Clinical Oncology
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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Toxicity Notes
Typical opioid adverse effects Existing data compared with
codeine only
Typical opioid adverse effects Similar to oxycodone
Potential for neuropathic pain;
low tendency to increase
dose; to be tested in large
studies
Typical opioid adverse effects Targeted therapy for
with less constipation constipation; to be
compared with common
laxative regimens
Headache, constipation, insomnia, No data on patients with
and withdrawal syndrome, each cancer
reported by ⬎ 20% of patients
Typical opioid adverse effects; More rapid than oral morphine
local for breakthrough pain; cost
effectiveness to be
established
cause decreased clearance of hydrocodone, which could lead to an
increase in hydrocodone plasma concentrations.
Hearing loss is a rare but serious adverse effect reported in pa-
tients receiving hydrocodone, especially at high doses. Hearing loss
did not resolve with discontinuation of hydrocodone or corticoste-
roid therapy.9
Studies of hydrocodone use in patients with cancer are lacking.
The only existing studies are those of the formulation combined with
paracetamol. In one study, efficacy and tolerability were comparable
for codeine plus paracetamol and hydrocodone plus paracetamol over
23 days of treatment in patients with moderate or severe chronic
cancer-related pain.10 In another trial, codeine and hydrocodone pro-
duced similar analgesia but fewer adverse effects than tramadol.11 In
October 2013, the US Food and Drug Administration approved the
use of sustained-release hydrocodone.12
Oxymorphone
Oxymorphone is one of the oxycodone metabolites that is more
lipid soluble than morphine or oxycodone, resulting in a more rapid
transfer across the blood-brain barrier. However, its oral bioavailabil-
ity is only 10% because of extensive first-pass elimination.13 In the
extended-release formulation, oxymorphone is inserted into an ag-
glomerated hydrophilic matrix, which releases the drug as water pen-
etrates the matrix to maintain therapeutic plasma levels during the
12-hour dosing interval. In 2011, the US Food and Drug Administra-
tion approved a new formulation of extended-release oxymorphone
designed to be crush resistant, with a reduced potential for tampering
and abuse.14
Oxymorphone is metabolized by the liver to 6-
hydroxymorphone and oxymorphone-3-glucuronide. Plasma lev-
els of these metabolites increased in a linear fashion after both
single- and multiple-dose administration.15 The effectiveness of
extended-release oxymorphone for the treatment of chronic can-
cer pain has been demonstrated in two studies. Patients with cancer
whose pain was previously stabilized on extended-release morphine or
extended-release oxycodone were safely and rapidly transitioned to a
JOURNAL OF CLINICAL ONCOLOGY
 New Opioids
lower-milligram dose of extended-release oxymorphone, which pro-
vided adequate pain relief with comparable tolerability. Equianalgesic
dose ratios of extended-release morphine and extended-release oxy-
codone were calculated to be 1.8:1 and 1.2:1, respectively. The adverse
effects were mild and typical of opioids (eg, nausea, drowsiness).16
Forty patients with cancer were administered oxymorphone or oxy-
codone to achieve adequate pain relief and then were transitioned to
the extended-release formulation for another 7 to 10 days. Patients
then underwent crossover (in a double-blind fashion) to the alterna-
tive medication for an additional 7- to 10-day period. Extended-
release oxymorphone and extended-release oxycodone provided
comparable analgesia. The equianalgesic ratio of extended-release
oxycodone to extended-release oxymorphone was found to be
2:1.17 A recent analysis assessed the effectiveness of oxymorphone
as an analgesic in a variety of chronic pain conditions. Oxymor-
phone and oxycodone at equipotent doses demonstrated similar
efficacy.18 Parenteral and oral formulations of oxymorphone may
be useful for easy dose titration and conversion. Dose conversion
from oxymorphone to other common opioids currently in use
requires further investigation.
MIXED OPIOIDS: TAPENTADOL
Centrally acting analgesics with a combined mechanism of action,
including ␮-opioid receptor activation with norepinephrine reuptake
inhibition, have recently been developed in an attempt to reduce the
tolerability issues with opioids while providing analgesia. Tapentadol
is a novel centrally acting analgesic characterized by both mechanisms
of action. With these characteristics, tapentadol should limit the po-
tential for addiction. Studies have shown that tapentadol is efficacious
in various acute and chronic pain conditions while also providing
better GI tolerability compared with oxycodone.19 Tapentadol under-
goes to a process of glucuronization and neither significantly inhibits
nor induces clinically important cytochrome enzymes. Because of its
low protein binding, displacement reactions are unlikely. Although
immediate-release tapentadol has been on the market since 2008, the
extended-release formulation was approved in 2011. Agents with
these latter properties have been found to be particularly effective in
neuropathic pain conditions and in potentiating the analgesic effects
of opioids.
Studies in patients with cancer with chronic pain are lacking. In
an open-label study, the efficacy and tolerability of tapentadol were
evaluated in the management of cancer pain.20 Fifty opioid-naive
patients with cancer with moderate to severe pain were observed for a
period of 4 weeks. Each patient initially received 50-mg doses of
slow-release tapentadol twice per day. On the basis of clinical re-
sponse, doses were then titrated to maintain adequate relief or limit
toxicity. Of the 50 patients enrolled, 39 completed the entire study,
and 11 discontinued treatment for various reasons. Pain intensity
significantly decreased from baseline during each of the weekly
intervals, whereas adverse effects did not change significantly, and
quality of life improved. The tendency to increase the dose over
time, as expressed by the escalation index, was low and was inde-
pendent of age, sex, and pain mechanism. This open-label study
was exploratory and limited by the small number of patients and
uncontrolled study design.
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Patients with cancer experiencing pain often require changes in
opioid therapy during the course of disease because of disease progres-
sion, pain characteristics, and prolonged use of opioids. The practice
of opioid switching is often successful,21 although the scientific evi-
dence remains poor because of a lack of controlled studies.22 The
antihyperalgesic effects of tapentadol23 could be potentially helpful in
states of hyperexcitation, such as those observed in patients who have
undergone multiple unsuccessful trials of opioids.
Data on conversion ratios between tapentadol and other opioids
are lacking. Results of a recent exploratory study suggested that a
conversion ratio between tapentadol and other opioids, expressed in
oral morphine equivalents, could be 1:3.3 in both directions, particu-
larly in patients who were switched for convenience rather than for an
inconvenient balance between analgesia and adverse effects. However,
the limited number of patients in this study does not allow for defin-
itive conclusion to be drawn. Thus, data should be interpreted with
caution, given the exploratory nature of the study and the small num-
ber of patients, and confirmation should be sought in future studies
with a larger number of patients.24 The potential use of tapentadol in
specific pain conditions, such as neuropathic pain, should also be
explored in future studies.
PRODUCTS TARGETING OPIOID-INDUCED CONSTIPATION
Several drug development strategies have attempted to provide differ-
ent analgesic mechanisms and reduce adverse effects by exploiting
anatomic barriers to drug distribution. In contrast to many opioid-
related adverse effects, which occur at the beginning of treatment and
then tend to disappear over time, constipation persists and represents
a clinically relevant problem during prolonged treatment with opi-
oids.25 A majority of patients with opioid-associated constipation
report some degree of negative impact on quality of life and thus are
more likely to use health care resources; they also report an impaired
ability to undertake daily activities and missing work.
The adverse effects of opioids on GI function are mediated by the
interaction of the drug with opioid receptors in the GI tract, although
numerous other factors may also contribute to constipation, particu-
larly in patients with advanced cancer.3 The most common drugs used
for relieving opioid-induced constipation are laxatives. Laxatives may
be ineffective when not used properly. These agents act on bowel
transit via different mechanisms but do not address the underlying
cause of opioid-induced constipation.
Oxycodone Plus Naloxone
In the last decade, attempts have been made to target the under-
lying mechanisms of opioid action in the GI tract by antagonizing
opioid receptors. Parenteral administration of naloxone produces a
general antagonism of opioid receptors, including those producing
the desired central analgesic effects. However, when naloxone is ad-
ministered orally, the systemic availability of naloxone is negligible
because of its extensive elimination by hepatic first-pass metabolism.
Thus, the antagonist effects should presumably be limited to intestinal
opioid receptors only, avoiding blockage of the desired central analge-
sic effects of opioids.
A number of pioneer studies have provided some evidence that
oral immediate-release naloxone provides relief from intestinal symp-
toms but only slightly reduces analgesic efficacy.25 A prolonged-
release formulation could potentially confer additional benefits, not
© 2014 by American Society of Clinical Oncology 1673
 Mercadante, Porzio, and Gebbia
only by ensuring continual intestinal opioid receptor antagonism, but
also by reducing the systemic levels of naloxone. The slow-release
preparation should avoid the overburdening of the hepatic enzymatic
system responsible for first-pass metabolism. As a consequence, the
combination of slow-release oxycodone plus naloxone prevents the
eventual loss of analgesic efficacy that would occur if naloxone were
not metabolized. Thus, a tablet combining prolonged release of oxy-
codone and naloxone could offer patients effective analgesia while
improving opioid-induced bowel dysfunction.
Most studies of combined oxycodone/naloxone have been con-
ducted in patients with conditions other than cancer.26 Only one
randomized study has been performed in the cancer population; 185
patients were enrolled onto a randomized, double-blind, double-
dummy, parallel-group study.27 Previous opioid and laxative medica-
tions were stopped at study entry, and patients were randomly
assigned to receive prolonged-release oxycodone plus naloxone or
prolonged-release oxycodone alone during the double-blind, double-
dummy phase. Bisacodyl was used as rescue medication for constipa-
tion. Patients were titrated up to 120 and 60 mg of prolonged-release
oxycodone and naloxone, respectively, or 120 mg per day of
prolonged-release oxycodone alone. Patients requiring doses
higher than 120 mg per day were withdrawn from the study. After
4 weeks, better intestinal function, scored by the bowel function
index, was observed with prolonged-release oxycodone plus nal-
oxone, and total laxative intake was 20% lower. Moreover, no
differences between frequency and dose of bisacodyl, used as laxa-
tive rescue medication, were found. The Brief Pain Inventory
short-form scores, use of analgesic rescue doses, quality of life, rate
of discontinuation, and adverse effects were comparable. Thus,
prolonged-release oxycodone plus naloxone tablets provide anal-
gesia equivalent to that provided by prolonged-release oxycodone
alone, with a similar adverse effect profile.
To demonstrate that there was no measurable loss of analgesia
with higher doses of oxycodone plus naloxone, doses were extended
up to 120 and 60 mg per day, respectively, with good pain control.27
Currently, the maximum allowed daily dose is 80 mg of oxycodone
and 40 mg of naloxone per day. New formulations have recently been
developed, which may allow the use of larger doses.
Additional research on the prolonged use of oxycodone plus
naloxone is needed, with a focus on specific issues regarding
prolonged-release oxycodone plus naloxone. For example, in patients
with cancer, it is often necessary to use high doses of opioids like
oxycodone. In an acute palliative care unit, approximately 20% of
patients required doses of oxycodone higher than 240 mg per day.28
No data exist on the use of oxycodone plus naloxone in this clinical
situation. Moreover, it has been reported that patients with a liver
shunt or liver disease may undergo withdrawal symptoms when
switching from oxycodone to the combination of oxycodone plus
naloxone because of the higher naloxone availability.29 The cost-
benefit ratio requires investigation,30 and additional efficacy and safety
data are needed in a larger number of patients with cancer for a longer
period of time.31
Of interest, new combinations of opioid-opioid antagonists and
new generations of opioid antagonists alone in formulations capable
of limiting penetration of the blood-brain barrier are in development.
These agents represent a new way to prevent and treat opioid-induced
constipation because they have the advantage, compared with the
usual laxatives, of addressing the underlying opioid receptor–
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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
mediated cause of bowel dysfunction. A cost-benefit analysis in com-
parison with laxatives should be performed.
Buprenorphine Plus Naloxone
Buprenorphine, a partial ␮-opioid receptor agonist, and naloxone, an
opioid antagonist, are combined in a 4:1 ratio. When this combination
is administered sublingually, the analgesic effects of buprenorphine
predominate, because the naloxone exerts no clinically significant
effect. However, the parenteral administration of this combination in
patients physically dependent on opioids produces withdrawal effects
because of the opioid antagonism of naloxone, thus reducing the
abuse potential of the drug combination.32 Therefore, the formulation
is similar to the formulation of buprenorphine-only sublingual tab-
lets, but with naloxone added to reduce the potential for abuse via the
intravenous route.
Substitution treatment for opioid drug dependence is the
claimed indication for this combination. Comprehensive manage-
ment should also include medical, social, and psychological treatment.
The presence of naloxone should deter intravenous misuse. Thus,
sublingual buprenorphine plus naloxone could be an appropriate
treatment for opioid dependence or opioid-abusing patients with
chronic pain. However, data on cancer pain are unavailable.
NEW DELIVERY SYSTEMS: RAPID-ONSET OPIOIDS FOR
BREAKTHROUGH PAIN
Breakthrough cancer pain has been reported to be a relevant problem
in patients with cancer with pain. Breakthrough cancer pain has been
defined as an acute transient worsening of pain in patients who have a
controlled baseline pain. Given the temporal characteristics of break-
through cancer pain (rapid onset and offset), management requires
drugs with a rapid onset, which cannot be achieved with oral mor-
phine. Breakthrough cancer pain is still typically managed with a
rescue dose of oral opioids. Of interest, no study has ever tested
breakthrough cancer pain other than as a comparator in studies in-
volving fentanyl preparations. With most breakthrough cancer pain
episodes peaking in intensity within a few minutes and lasting for 30 to
60 minutes, speed of onset is crucial for effective pain management.
Different technologies have been developed to provide fast pain relief
with potent opioid drugs such as fentanyl delivered by noninvasive
routes. After oral transmucosal fentanyl was shown to be superior to
oral morphine and placebo,33 a new generation of delivery systems
was developed to improve availability through the mucosal barrier
and overcome some practical problems. These new products have
been shown to be superior to placebo and oral morphine.34,35
Fentanyl Buccal Tablet
The fentanyl buccal tablet facilitates rapid absorption of fentanyl
through the oral mucosa using an enhanced effervescent absorption
technology.36 Absorption is optimized by the effervescent reaction
that produces shifts in pH within the microenvironment between a
dissolving tablet and the buccal mucosa.
Sublingual Fentanyl
Subsequently, a sublingual formulation of fentanyl, which dis-
solves in minutes, was developed; the onset of action is similar to that
of the fentanyl buccal tablet. This formulation involves a small tablet
JOURNAL OF CLINICAL ONCOLOGY
 New Opioids

made of a mix of active drug particles and water-soluble carrier parti-
cles coated with a mucoadhesive agent.37 More recently, a sublingual
spray has been developed.38 Finally, a buccal soluble film has been
marketed. The bioerodible mucoadhesive delivery technology con-
sists of two different layers made of water-soluble polymeric films, one
with bioadhesive containing the active substance and one inactive.
The inactive layer isolates the bioadhesive layer from the buccal cavity,
minimizing the amount of fentanyl that is swallowed.39
Intranasal Fentanyl
The intranasal administration of fentanyl may have some
advantages (eg, in patients with mucosal damages or salivary dys-
function).33 Two formulations of nasal fentanyl have been devel-
oped: an aqueous solution and a pectin-based drug delivery system
in the form of a gel designed to be applied to mucosal surfaces to
optimize absorption.40
These delivery systems provide fast and effective analgesia within
5 to 15 minutes, with the nasal products providing the most rapid
effect. Many studies have shown that the new delivery systems provide
fast and efficient analgesia in comparison with oral opioids or placebo
for the management of breakthrough cancer pain.33-35 In most trials,
however, an enriched design was used, excluding patients who did not
respond to dose titration or when maximum doses were achieved.
Moreover, the indication to titrate the doses is derived from studies
designed for other purposes (eg, to compare fentanyl products with
placebo or oral opioids). The authors of these studies concluded that
there was no relationship between opioid doses used for background
pain and effective doses achieved after dose titration of rapid-onset
opioids. Thus, current recommendations are for personalized titra-
tion of the dose. However, there is no proof that the use of opioid
titration is more efficient than other approaches, such as the use of
doses proportional to the basal opioid regimen.41,42 It is important to
note that fentanyl preparations might be associated with acute neuro-
cognitive changes related to rapid peak brain level, potentially leading
to falls and problems with some skill-requiring activities, such as
driving. More research is needed to better understand the safety of
these products.
Concerns have been raised regarding the cost effectiveness of
these products in comparison with oral morphine. In some com-
parative studies with oral opioids, the number of doses needed to
obtain relief at 15 minutes was ⱖ 10.43 National Institute for
Health and Care Excellence guidelines did not provide evidence to
suggest that fentanyl products were more effective than oral mor-
phine for the management of breakthrough pain, at least at certain
time intervals after administration. The cost impact of recom-
mending fentanyl over oral morphine would be considerable and
could therefore not be justified. As a consequence, fast-acting
fentanyl as first-line rescue medication was not suggested.44 Over-
all, there is a lack of pharmacoeconomic studies for breakthrough
pain management with rapid-onset opioids, at least as primary
outcome in a clinical setting. For instance, a recent analysis incor-
porating some relevant studies revealed that the fentanyl prepara-
tions provided superior pain relief as compared with placebo
within in the first 30 minutes after dosing (compared with placebo,
fentanyl buccal tablet provided 83% probability of superior pain
relief; sublingual fentanyl, 66%; and oral transmucosal fentanyl,
73%), and oral morphine performed slightly better than placebo
(56% probability).45
Additional studies are warranted to assess the net benefit
of fentanyl preparations versus oral opioids to assist decision mak-
ing by patients, clinicians, and payers.34 It is likely that appropri-
ate dosing may enhance the advantages of such products when
used at proportional doses, because this approach may produce
better and rapid efficacy while maintaining safety.46 Addiction
risks with long-term use of these products should be assessed in
future studies.
DISCUSSION
New opioids have been recently marketed, generally at higher costs
in comparison with existing ones. Studies of hydrocodone in pa-
tients with cancer are lacking, and no evidence exists that the
efficacy of oxymorphone differs from that of other opioids. Tap-
entadol may be useful in specific pain conditions, such as neuro-
pathic pain, but this potential should be explored in future studies.
The oxycodone plus naloxone combination may represent a new
way to prevent and treat opioid-induced constipation, but a cost-
benefit analysis in comparison with laxatives should be performed.
Although sublingual buprenorphine plus naloxone could be of
benefit for the treatment of opioid dependence or opioid-abusing
patients with chronic pain, data on cancer pain are unavailable.
Finally, fentanyl preparations are highly effective in the manage-
ment of breakthrough pain. However, additional studies are war-
ranted to assess the net benefit of fentanyl preparations versus oral
opioids to assist decision making by patients, clinicians, and pay-
ers. Despite the pending availability and therapeutic opportunities
associated with new drugs and technologies, their benefits and
liabilities should be determined by the individual physician and the
individual patient experiencing pain.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Sebastiano Mercadante
Collection and assembly of data: Giampiero Porzio, Vittorio Gebbia
Manuscript writing: All authors
Final approval of manuscript: All authors

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