Mechanisms of Opioid-
Induced Tolerance and
yyy Anna DuPen, MN, ARNP,* Danny Shen, PhD,‡and
Mary Ersek, PhD, RN†
Opioid tolerance and opioid-induced hyperalgesia are conditions that
negatively affect pain management. Tolerance is defined as a state of
adaptation in which exposure to a drug induces changes that result in
a decrease of the drug’s effects over time. Opioid-induced hyperalge-
sia occurs when prolonged administration of opioids results in a
paradoxic increase in atypical pain that appears to be unrelated to
the original nociceptive stimulus. Complex intracellular neural mech-
anisms, including opioid receptor desensitization and down-regula-
tion, are believed to be major mechanisms underlying opioid toler-
ance. Pain facilitatory mechanisms in the central nervous system are
known to contribute to opioid-induced hyperalgesia. Recent research
indicates that there may be overlap in the two conditions. This article
reviews known and hypothesized pathophysiologic mechanisms sur-
rounding these phenomena and the clinical implications for pain
© 2007 by the American Society for Pain Management Nursing
Opioid analgesics continue to be the mainstay of pharmacologic treatment of
moderate to severe pain. Many patients, particularly those with advanced can-
cer, require chronic high-dose opioid therapy. Achieving clinical efficacy and
tolerability of such treatment regimens is sometimes hindered by two opioid-
related phenomena. The first is tolerance, which is manifested clinically by the
need for increasing opioid dosages over time to maintain the same level of pain
relief; this increased need is not explained by disease progression. A second
problem that arises is the more recently recognized phenomenon of opioid-
induced hyperalgesia (Sjogren et al., 1998). In this situation, prolonged admin-
istration of opioids results in a paradoxic increase in atypical pain that appears
to be unrelated to the original nociceptive stimulus.
Opioid-induced tolerance and hyperalgesia have been documented in both
animal and human studies. They can develop after administration of several
types of opioids delivered via various routes, doses (i.e., ultra-low through high
dosages), and administration schedules (i.e., intermittent vs. continuous) (Angst
& Clark, 2006; Mao, 2006; Ossipov et al., 2005). Cellular changes associated
with these phenomena have been identified at many anatomic sites, including
afferent neurons, the spinal cord, brain, and the descending modulatory path-
way (Gardell et al., 2006; King et al., 2005; Mao et al., 2002; Ossipov et al., 2005;
Terman et al., 2004).
From the *Pain and Palliative
Care Research Department, and
†Center for Nursing Excellence,
Swedish Medical Center, Seattle,
Washington; and‡Departments of
Pharmacy and Pharmaceutics,
University of Washington School of
Pharmacy, Seattle, Washington.
Address correspondence to Anna
DuPen, MN, ARNP, Pain and
Palliative Care Research Department,
Swedish Medical Center, 500 17th
Ave, Providence Professional Building
Suite 405, Seattle, WA 98122-5711.
© 2007 by the American Society
for Pain Management Nursing
Pain Management Nursing, Vol 8, No 3 (September), 2007: pp 113-121
Significant clinical challenges arise from opioid-
induced tolerance and hyperalgesia. More effective
pain treatment can be achieved when these conditions
are recognized and managed. Although the mecha-
nisms underlying opioid-induced tolerance and hyper-
algesia are not completely understood, research has
begun to reveal some of the complex factors that are
associated with these phenomena. The purpose of
the present article is to describe both the estab-
lished and the hypothesized mechanisms underlying
opioid-induced tolerance and hyperalgesia. The clin-
ical implications of these mechanisms and their pos-
sible prevention and treatment also are discussed.
OPIOID RECEPTOR PHYSIOLOGY
A discussion of opioid tolerance is best prefaced with
a review of opioid receptor physiology. Researchers
have identified three types of opioid receptors: mu,
delta, and kappa receptors. These receptors are dis-
tributed in various locations within the spinal cord and
brain structures. Figure 1 shows the distribution of
opioid receptors in the brain of a guinea pig. Mu
opioid receptors are highly concentrated in the outer
laminae of the dorsal horn of the spinal cord, whereas
throughout the dorsal horn (Quirion, 1984; Quirion et
al., 1983). Kappa opioid receptors are concentrated in
the outer laminae of the dorsal horn of the lumbosa-
cral cord and are closely associated with neural input
are diffusely distributed
from the visceral structures (Quirion, 1984; Quirion et
al., 1983). Two areas of the brainstem—the rostral
ventromedial medulla (RVM) and the periaqueductal
gray (PAG)—express high levels of mu opioid recep-
tors; delta and kappa receptors are also expressed,
albeit at much lower levels (Mansour et al., 1987;
Mansour et al., 1995). Studies have demonstrated mu
and some delta opioid receptors on neurons that arise
from the PAG or RVM and descend to the spinal cord
where they inhibit pain transmission (Van Bockstaele
et al., 1996).
Clinically available and experimental opioids have
differing potency and efficacy at the various opioid
receptors. The overall action of a particular opioid is
the sum effect of activation of all the relevant recep-
tors. Most of the opioids that are currently used in
clinical practice are predominantly mu agonists (al-
though some also bind at delta or kappa receptors or
both). There are at least seven “subtypes” of the mu
receptor (Pasternak, 2001), and each opioid may have
different affinities for the various mu receptor sub-
types. Tolerance may develop separately at each mu
receptor subtype in response to a particular opioid.
When a patient is switched from one opioid to an-
other, the “new” opioid may have a different selectiv-
ity for the individual mu receptor subtypes, which
explains “incomplete” cross-tolerance and offers a way
to overcome tolerance.
This difference in how opioids interact with the
mu receptor subtypes and/or their ability to activate
the other opioid receptor types could explain or pre-
dict clinical differences in the pharmacologic effect of
one opioid compared with another. Moulin et al.
(1988) studied tolerance in morphine versus levorpha-
nol, an opioid that is active at all three opioid recep-
tors. Pretreatment with levorphanol in rats caused
tolerance to morphine and levorphanol, but pretreat-
ment with morphine caused tolerance only to mor-
phine and not to levorphanol, indicating that receptor
selectivity influences tolerance (Moulin et al., 1988).
More recently, investigators have postulated that the
ability of methadone to differentially activate delta
opioid receptors may be a contributing factor to its
incomplete cross-tolerance in patients who had be-
come tolerant to mu opioids such as morphine (Lynch,
Some investigators have postulated that genetic
variations in receptors, often referred to as genetic
polymorphism, can account for interindividual differ-
ences in pain sensitivity, opioid analgesic response,
and risk of psychologic dependence (Bond et al., 1998;
Estfan et al., 2005; Thomsen et al., 1999). Approxi-
mately 500 genes have been identified that influence
pain in animal and human studies, with about 100
FIGURE 1.yImage of guinea pig brain; red areas repre-
sent highest density, yellow areas represent moderate
density, and blue, purple, and white represent low density
of opioid receptors. Reprinted with permission from So-
lomon H. Snyder, MD, Department of Neuroscience,
Johns Hopkins Medical School.
DuPen et al.
variations in the human mu opioid receptor gene
alone (Ross et al., 2006). At present, the functional
significance of many of these pain-related and opioid
receptor genetic variants has not been fully elucidated.
For example, the A118G genetic variant of the mu
opioid receptor, which results in a change in amino
acids from asparagine to aspartate at position 40, has
been studied in both pain (Hirota et al., 2003; Lotsch
et al., 2002; Lotsch et al., 2002; Ross et al., 2005) and
addiction (Bergen et al., 1997; Bond et al., 1998; Li et
al., 2000; Sander et al., 1998; Town et al., 1999), with
conflicting reports on its relationship to morphine
potency or its association with risk of substance abuse.
A recent study explored the influence of variations in
genes that encode the mu opioid receptor and its
regulatory proteins on opioid response in a cancer
patient population. There were no significant differ-
ences in the frequency of several variants of mu opioid
receptor genes between patients responsive to mor-
phine and those intolerant of morphine. There were,
however, significant differences in frequency of two
genetic variants (i.e., stat6, mu opioid gene transcrip-
tional factor; and ?-arrestin2, intracellular regulatory
protein) between patients who required a switch from
morphine to an alternative opioid compared with
those who obtained adequate analgesia with morphine
(Ross et al., 2005). These differences suggest that ge-
netic variations among individuals influence clinical
responses to morphine and possibly other opioids.
Opioid-induced tolerance is described in the simplest
pharmacologic terms as a shift to the right in the
dose-response curve; in other words, a higher dose is
required over time to maintain the same level of anal-
gesia. At times, progressive disease is the reason for
higher opioid requirements (Collin et al., 1993; Foley,
1993). Other causes of increased opioid needs are
pharmacokinetic or pharmacodynamic changes. Phar-
macokinetic changes occur, for example, if the drug
up-regulates the activity of a metabolic process that
represents a major pathway for its elimination from
the body. Enzyme induction results in a gradual reduc-
tion in plasma drug concentration while the daily
opioid dose remains unchanged. Pharmacodynamic
tolerance occurs when a decline in drug effect cannot
be attributed to pharmacokinetic factors but instead
reflects drug-activated changes in the response of the
neural systems. For our purposes, “opioid tolerance”
refers to pharmacodynamic tolerance.
Two major theories of opioid tolerance involve
changes in opioid receptors. One theory purports that
receptors undergo changes that result in decreased
receptor activation, or desensitization, with prolonged
exposure to opioids. The other line of evidence sug-
gests that opioid receptor down-regulation is at least
partially responsible for the development of tolerance.
The desensitization mechanism involves changes
in the physiology of the opioid receptors. These re-
ceptors belong to the family of G protein–coupled
receptors (GPCRs). When the opioid is bound to the
receptor, the associated G protein becomes “acti-
vated.” Activation of G proteins eventually leads to
decreasing excitability along the cell membranes of
neurons in the pain pathways. This action occurs
through a reduction in cyclic adenosine monophos-
phate (cAMP), leading to a suppression of Na? and
Ca? channels and resulting in analgesia (Figure 2).
Over time, alterations in the G protein–mediated
mechanism can lead to decreased analgesia through
opioid receptor desensitization (Ferguson et al., 1998;
Luttrell & Lefkowitz, 2002; Perry & Lefkowitz, 2002;
Raehal & Bohn, 2005; Shen & Crain, 1990; Terman et
al., 2004; Wang et al., 2005; Yoburn et al., 2003). In
animal models, this desensitization occurs when intra-
cellular regulatory proteins or enzymes, such as GPCR
kinases, ?-arrestins, and adenylyl cyclase, are activated
by opioids in such a way that they “decouple” the
opioid receptor from the G protein or produce a
“switch” in coupling of the receptor to a “nonanalge-
sic” G protein, subsequently decreasing analgesic ac-
tivity. Receptor desensitization has been previously
associated with morphine tolerance in rats (Noble &
Cox, 1996; Sim et al., 1996), but more recent reviews
underscore how much is left to be learned about these
complex intracellular mechanisms (Raehal & Bohn,
FIGURE 2.ySchematic of opioid receptor mechanism.
Opioid Tolerance and Hyperalgesia
A second mechanism believed to be responsible
for opioid tolerance occurs via internalization of the
opioid receptor from the cell membrane. The density
of opioid receptors located on the cell membrane is
governed by endocytosis, whereby the cell membrane
closes around the receptor, effectively creating a bub-
ble of cell membrane around the receptor and drawing
it into the body of the cell. Once inside the intracel-
lular environment the receptor can no longer function
and is effectively down-regulated. Rats lacking one of
these down-regulators (?-arrestin2) continue to have
prolonged morphine-induced analgesia, whereas their
counterparts that do have this down-regulator develop
“tolerance” to the analgesic effects (Bohn et al., 2002;
Bohn et al., 1999). Despite this evidence, some re-
searchers have suggested that increased internaliza-
tion may actually decrease tolerance by getting desen-
sitized receptors off the membrane and causing
resensitization through new or recycled receptors be-
ing substituted (Finn & Whistler, 2001).
Various opioid agonists (e.g., morphine, metha-
done, fentanyl) have been shown to differ in their
ability to desensitize or down-regulate opioid recep-
tors (Arden et al., 1995; Sim-Selley et al., 2000; Ya-
baluri & Medzihradsky, 1997). Some of these differ-
ences have been attributed to the “intrinsic efficacy”
of the opioid agonist. Each opioid has a given level of
intrinsic efficacy for the various opioid receptors. In-
trinsic efficacy is a conceptual parameter that relates
the number of receptors occupied to the magnitude of
the receptor-mediated response. To generate a given
effect, it is necessary to occupy a number of receptors
out of the total population, the so called “fractional
receptor occupancy” (Chavkin & Goldstein, 1982;
Mercadante, 1999). The number of receptors that
need to be occupied to create an analgesic effect is
believed to be inversely proportional to the intrinsic
activity; in other words, the larger the number of
unoccupied receptors (receptor reserve) that exist
when a drug achieves analgesia, the greater the intrin-
sic efficacy of the drug (Chavkin & Goldstein, 1984;
Duttaroy & Yoburn, 1995; Ivarsson & Neil, 1989; Sos-
nowski & Yaksh, 1990).
In general, continuous treatment with opioids
with lower intrinsic efficacy, such as morphine, have
been known to cause a larger rightward shift in dose
response (i.e., tolerance) (Saeki & Yaksh, 1993). Ani-
mal studies have shown that chronic treatment with
high-efficacy opioids that have a significant receptor
reserve, such as fentanyl, down-regulate fewer recep-
tors (Sosnowski & Yaksh, 1990). However, recent
studies show high-efficacy opioids actually activate
more receptor-desensitizing substances (G protein–
coupled receptor kinases) than low-efficacy opioids
(Terman et al., 2004), leaving us again with more
complexity than clarity on these opioid-related intra-
Opioid-induced hyperalgesia is a condition manifested
clinically as hyperesthesia (i.e., dramatically increased
sensitivity to painful stimuli) and/or allodynia (i.e.,
pain elicited by a normally nonpainful stimulus). It
occurs in some patients (and, in laboratory studies,
animals) receiving chronic opioid therapy; the abnor-
mal pain often arises from an anatomically distinct
region and is of a different quality than the original
pain problem (Ossipov et al., 2005). Clinical reports
dating back to the late 19th century documented that
hyperalgesia was associated with opioid dependence.
Later clinical observations and studies suggested that
pain sensitivity differs between persons with opioid
addiction and those who are not addicted (Compton,
1994; Doverty et al., 2001). In the 1940s, hyperalgesia
also was described as part of the opioid withdrawal
syndrome. In the past decade, research indicated that
hyperalgesia also occurred in the context of short-term
and continuous therapy in which physical depen-
dence and withdrawal did not play a role (Angst &
Several mechanisms associated with opioid-
induced hyperalgesia have been identified. Glutamate-
associated activation of N-methyl-D-aspartate (NMDA)
receptors causes spinal neuron sensitization; this
pronociceptive mechanism has been implicated in the
development of neuropathic pain and opioid-induced
hyperalgesia. The ability of NMDA receptor antago-
nists such as MK801 to block opioid-associated hyper-
algesia provides further evidence that NMDA recep-
tors are involved in hyperalgesic states (King et al.,
2005; Mao, 2006; Ossipov et al., 2005).
Other studies have documented that hyperalgesia
results from increased excitatory peptide neurotrans-
mitters, such as cholecystokinin (CCK), which are
released from neurons in the RVM and activate spinal
pathways that up-regulate spinal dynorphin. Both of
these substances act as pronociceptive agents (Dour-
ish et al., 1988; Gardell et al., 2002; Vanderah et al.,
2000; Vanderah et al., 2001; Xu et al., 1992). These
and other excitatory neurotransmitters are believed to
cause “central sensitization” that result in hypersensi-
tivity of the spinal cord to nociceptive inputs from the
periphery. In other words, pain signals being transmit-
ted into the spinal cord become amplified as a result of
the action of these neurotransmitters.
DuPen et al.
OPIOID-INDUCED TOLERANCE AND
HYPERALGESIA: TWO SIDES OF THE
The major clinical manifestation of opioid-induced tol-
erance and that of hyperalgesia are the same; that is,
increasing opioid doses are necessary to achieve ade-
quate analgesia (Angst & Clark, 2006; King et al., 2005;
Mao, 2006). Moreover, there are similarities in the
mechanisms that cause tolerance and hyperalgesia. For
example, CCK-mediated changes in the descending
modulatory pathways appear to contribute to both
opioid-induced tolerance and hyperalgesia (King et al.,
2005). There also is evidence that tolerance and hy-
peralgesia share common cellular mechanisms that are
related to changes in NMDA receptors (Mao et al.,
1994; Mao et al., 2002).
The similarities between mechanisms causing tol-
erance and hyperalgesia suggest that some targeted
therapies can prevent or reverse both phenomena.
While this strategy has been shown to be effective in
preclinical and clinical studies, Mao urged caution
with this approach (Mao, 2002; Mao, 2006). He
pointed out that hyperalgesia is characterized by dif-
ferent clinical features than tolerance. These features
include pain intensity that is higher than the severity
of the original pain problem, pain that is poorly de-
fined in terms of quality and location, and changes in
pain threshold and tolerability. These distinct features
indicate that at least some of the cellular mechanisms
underlying tolerance and hyperalgesia differ between
the two entities. Hyperalgesia represents increased
sensitivity to pain, whereas tolerance may reflect de-
creased sensitivity to opioids. Most importantly, un-
like tolerance, opioid-induced hyperalgesia would
worsen after an increase in opioid dose, whereas pain
related to tolerance would be relieved by an increase
in opioid dose (Mao, 2002; Mao, 2006).
Pain management specialists are frequently called to
consult on cases involving opioid tolerance or toxici-
ties. Strategies for clinical management must be based
on the current understanding of the complex mecha-
nisms underlying these problems. Some strategies,
such as the use of opioid-sparing therapies and opioid
rotation, are currently used to prevent and treat toler-
ance and hyperalgesia, although the evidence support-
ing these practices is lacking. Other strategies such as
the use of concomitant low-dose opioid antagonists to
suppress G protein switching, inhibition of ?-arrestin2
to prevent down-regulation, or the use of CCK and
NMDA receptor antagonists to suppress pain facilita-
tion pathways are still in preclinical or early clinical
studies. Pain management nurses should understand
the scientific basis for current and emerging therapies.
One of the most commonly used strategies to
prevent opioid tolerance and hyperalgesia is the use of
adjuvant drug therapies such as anticonvulsants and
antidepressants, as well as nondrug therapies such as
heat, cold, and exercise programs. This approach is
the cornerstone of the “opioid-sparing” principle,
which aims to minimize opioid doses while providing
optimal pain relief. Although there is no hard evidence
that receptor desensitization or down-regulation oc-
curs with more intensity at higher doses of opioids,
many pain specialists accept the premise that an opi-
oid-sparing treatment plan is the first step in proac-
tively minimizing side effects and opioid tolerance (Ho
et al., 2006; Lauretti et al., 1999; White, 2005), despite
evidence that challenges this principle (Kloke et al.,
Opioid rotation is widely used as a treatment
option to take advantage of “incomplete cross-toler-
ance” to recapture efficacy in a patient experiencing
significant opioid tolerance or unusual sensitivity to
opioid side effects. Several reports have documented
success with this strategy (De Stoutz et al., 1995;
Drake et al., 2004; Indelicato & Portenoy, 2002; Kloke
et al., 2000; Thomsen et al., 1999), although the re-
search evidence is weak, given the poor design and
small samples that characterize studies evaluating this
clinical maneuver (McNicol et al., 2003; Quigley,
Combining opioids with low-dose opioid antago-
nists to prevent hyperalgesia and tolerance is an active
area of study that offers some promise that the cellular
mechanisms of tolerance might be circumvented.
Wang et al. (2005) and Terner et al. (2006) demon-
strated a significant attenuation in opioid tolerance
when low-dose naltrexone was added to a morphine
regimen in rats. A recent randomized controlled trial
(RCT) in 350 osteoarthritis patients showed a statisti-
cally significant advantage in pain relief over time for
patients treated with the combination of oxycodone
and naltrexone over oxycodone alone, a clinical out-
come that has been suggested to result from the sup-
pression of G protein switching (Chindalore et al.,
2005; Crain & Shen, 2000; Wang et al., 2005). With
further validation, this drug combination approach
could be offered as a pre-emptive strategy in managing
patients at risk of developing significant opioid toler-
The ability of CCK antagonists to prevent the
development of hyperalgesia and tolerance has been
suggested (King et al., 2005), largely based on studies
with the CCK antagonist proglumide in animal models
Opioid Tolerance and Hyperalgesia
(Tang et al., 1984; Watkins et al., 1984). In several
small clinical studies (Bernstein et al., 1998; McCleane,
2004; McCleane, 1998; McCleane, 2003; Price et al.,
1985), proglumide appeared to enhance opioid anal-
gesia; whether the augmentation was attributed to
reversal of tolerance and/or amelioration of hyperalge-
sia is debatable. To date, there have been no RCTs that
fully document the efficacy of proglumide as a pro-
moter of opioid analgesia. Moreover, studies in pa-
tients with documented opioid tolerance or hyperal-
gesia would be needed to demonstrate the putative
counteractive effects of CCK antagonists on opioid-
induced tolerance and hyperalgesia. Thus additional
research is needed before CCK antagonists can be
recommended in clinical practice (McCleane, 2004).
Blockade of the NMDA receptor has been shown
to reduce opioid-induced hyperalgesia and retard opi-
oid tolerance development in both animal models and
human case reports (Celerier et al., 2000; Clark &
Kalan, 1995; Davis & Inturrisi, 1999; Eilers et al., 2001;
Elliott et al., 1994; Gorman et al., 1997; Haley, Sullivan,
& Dickenson, 1990; Mao et al., 1995; Mercadante,
1996). However, one recent RCT in chronic pain pa-
tients failed to demonstrate a reduction in hyperalgesia
or tolerance after three months of concurrent treat-
ment with morphine and dextromethorphan (an
NMDA receptor antagonist) compared with with mor-
phine alone (Galer et al., 2005). Methadone, a mu
agonist which also is an NMDA receptor antagonist,
has been examined as an agent that can potentially
prevent tolerance and hyperalgesia (Morley, 1998).
Several clinical reports indicate that rotation to meth-
adone from other opioids enhances analgesia (Benitez
del Rosario et al., 2004; Quigley, 2004; Vigano et al.,
1996). In contrast, enhanced pain sensitivity in opioid
addicts who are receiving methadone maintenance
therapy is well documented (P. Compton et al., 2001;
Doverty et al., 2001; Mao, 2006). Thus, the role for
methadone in the setting of hyperalgesia awaits fur-
Ongoing investigations to further define the vari-
ants of genes encoding the mu opioid receptor and on
the key proteins involved in receptor desensitization
and down-regulation are intriguing. If there were a
simple way to test for these genetic differences in
patients in the future, clinicians might have a more
rational approach to optimal drug selection and drug
rotation in opioid therapy.
Clinical strategies to prevent or manage hyperal-
gesia start with early identification of the problem.
Hyperalgesia should be suspected whenever repeated
dose escalation fails to provide the expected analgesic
effects or when there is an unexplained pain exacer-
bation after an upward titration of opioid. The index of
suspicion is higher if the increased pain is consistent
with hyperesthesia or allodynia and other obvious
causes such as disease progression or acute insult are
ruled out. Hyperalgesia should be treated by reducing
dose or eliminating the offending opioid. Theoreti-
cally, a reduction in the opioid dose with or without
adding a replacement opioid or a gradual rotation to an
alternate opioid would result in a decrease in pain. As
with opioid tolerance, no RCTs exist demonstrating
the superiority of one opioid over another in avoiding
FUTURE DIRECTIONS AND SUMMARY
The molecular mechanisms underlying opioid tolerance
and opioid-induced hyperalgesia are being investigated
in research laboratories throughout the world. Based on
the research accomplished to date, it appears that these
two phenomena may be related but also have distinct
features. Future scientific efforts will be directed at deep-
ening our understanding of how adaptive responses by
multiple neural systems work together to counteract the
analgesic efficacy of commonly used opioids. Future
pharmaceutical development will focus on blocking the
facilitatory mechanisms that produce these adaptive
changes in the endogenous nociceptive and antinocicep-
tive systems in response to continual exposure to an
opioid analgesic. Development of diagnostic tests for
biomarkers or genotypes that will allow identification of
the opioid best suited to an individual patient’s profile
seems attainable within the not-too-distant future.
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