CNS Drugs (2019) 33:943–955

https://doi.org/10.1007/s40263-019-00660-0

CURRENT OPINION

Opioid‑Induced Tolerance and Hyperalgesia

Sebastiano Mercadante1,2 · Edoardo Arcuri3 · Angela Santoni4

Published online: 1 October 2019

© Springer Nature Switzerland AG 2019

Abstract
Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use
of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and
dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the
same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry,
and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a
state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather
than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independ-
ent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is
mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional
techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms produc-
ing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques
utilized in these circumstances.

Key Points
The development of tolerance is the main problem dur-
ing opioid treatment as it requires increased opioid drug
doses to achieve the previous level of analgesia.
Mechanisms of opioid tolerance include drug-induced
adaptations or allostatic changes at the cellular, circuitry,
and system levels.
Dose escalation in long-term opioid therapy might result
in a state of hypersensitivity to painful stimuli, known as
opioid-induced hyperalgesia (OIH), resulting in exacer-
bation of pain rather than pain relief.
Possible strategies to mitigate, reverse, or prevent opioid-
induced tolerance and OIH are the use of adjuvant
analgesics or opioid switching.
1 Introduction
Chronic pain is a major health issue that impacts quality of
life. About one-third of the population in western countries
experiences chronic pain, with the cost related to this esti-
mated to be about $US600 billion annually [1, 2]. Despite
the development of new analgesic substances for treating
pain, opioids still remain the most frequent class of analge-
sics used in various clinical settings. Opioids are very potent
and efficacious drugs, traditionally used for both acute and
chronic pain conditions. When opioids are used for chronic
pain, they are administered for a prolonged time period.
However, the use of opioids is frequently associated with
the occurrence of adverse effects or clinical problems.
Long-term administration of morphine and other opioids
can lead to the development of analgesic tolerance. Toler-
ance has been defined as a reduction in effect following
prolonged drug administration that results in a decrease of

2
* Sebastiano Mercadante Palliative/Supportive Care and Rehabilitation, MD Anderson,
terapiadeldolore@lamaddalenanet.it Houston, TX, USA
3
Edoardo Arcuri Regina Elena Cancer Institute, Rome, Italy
edoardo.arcuri@fastwebnet.it 4
University of Rome, Rome, Italy
Angela Santoni
angela.santoni@uniroma1.it
1
Main Regional Center of Supportive/Palliative Care, La
Maddalena Cancer Center, Palermo, Italy

Vol.:(0123456789)
944
drug potency, characterized by a shift to the right in the
dose–response curve. The term tolerance itself has been
used to describe multiple processes. While associative tol-
erance is related to conditioning, pharmacological tolerance
is related to specific drug actions. Pharmacological tolerance
may be dispositional, due to pharmacokinetic changes or
pharmacodynamics. The latter is more common and char-
acterized by a decline in analgesia related to complex pro-
cesses of neural adaptation. There is a large intra-individual
and inter-individual variability in the development of toler-
ance. This phenomenon develops at varying rates and can
occur both after short-term dosing or accrue more gradually
with long-term dosing. Tolerance to adverse effects has its
own favorable aspect as it allows the therapeutic window to
be enlarged. From a clinical perspective, the development
of tolerance may become the ‘driving force’ for dose esca-
lation, which can be constant during long-term administra-
tion and can have an accelerated phase at the beginning of
the treatment as well as at other times during the course
of treatment. Tolerance may be a major contributing factor
in declining opioid effects, and may create a situation of
poor responsiveness if adverse effects occur as the dose is
increased [3].
There are some factors that influence the development of
tolerance, including the interactions between the drug and
the opioid receptors, doses, and frequency of administra-
tion. Many mechanisms contribute to opioid tolerance at a
behavioral level. These processes include the upregulation of
drug metabolism (i.e., metabolic tolerance), desensitization
of receptor signaling, downregulation of receptors, and com-
pensatory/opponent processes [4]. From a clinical perspec-
tive, analgesic tolerance is noteworthy, as the management
of such patients during acute episodes of care is a challenge
because they will have a significantly longer length of hos-
pital stay, are more likely to be readmitted within 30 days,
and have a higher risk of mortality and co-morbidities [5].
Indeed, the progressive increase of opioid doses can induce
or exacerbate undiagnosed opioid-induced hyperalgesia
(OIH), which in turn increases the occurrence of behavioral
analgesic tolerance and is often misdiagnosed as a progres-
sion of disease-producing pain.
Tolerance is a relevant component of dependence and
addiction liability. The US Food and Drug Administration
(FDA) defines tolerance as an opioid dose of 60 morphine
milligram equivalents daily [6]. Indeed, tolerance to opioid-
induced respiratory depression is the other face of the coin,
because opioid tolerance can result in protection against a
fatal complication with increasing doses. However, it can
also cause an increase in mortality when addicted patients
take the same dose of opioid in a different environment/
context [7] or when they relapse after a period of abstinence.
In these patients, in fact, the level of tolerance abates and
an opioid dose may induce life-threatening consequences.
S. Mercadante et al.
Another problem with tolerance is that the management of
pain in opioid addicts is extremely challenging, as metha-
done-maintained patients are more refractory to the analge-
sic effects of opioids just because of the high level of toler-
ance [8].
Opioids generate opponent processes in both nociceptive
circuits and circuits modulating mood. The involvement of
different circuits contributes to the production of an addicted
state favoring the hedonic aspects of drug taking. Among
these adverse effects, prolonged opioid therapy is associated
with tolerance and OIH, which are relevant for the inevita-
ble consequences on the clinical responses. While the pro-
gressive decrease in analgesia produced by an opioid given
long-term may be compensated for with an increased dose to
achieve the same level of the previous analgesia, with OIH
there is a development of hypersensitivity to painful stimuli
associated with opioid therapy, resulting in exacerbation of
pain sensation rather than relief from pain.
It is relevant to distinguish between tolerance and OIH
[3]. Tolerance is exhibited with most opioid effects but not
to miosis and constipation. The increase in doses overcomes
this problem and the patient will be relieved of his pain. In
OIH there is a state of nociceptive sensitization induced by
an acute as well as a prolonged exposure to opioids. The
level of pain experienced might be the same or often might
be different. However, it cannot be resolved by increasing
the dose of the drug, which instead can aggravate the pain.
This phenomenon can be relieved only by decreasing the
dose of opioid or discontinuing it while using other strate-
gies to compensate the underlying pain condition [9]. This
clinical eventuality is quite complex, as a negative feedback
loop can be elicited so that the development of tolerance
often induces physicians to increase opioid doses. This
decision, in turn, facilitates the development of OIH. The
clinical implications are that dose escalation in long-term
opioid therapy might cause OIH, producing a vicious cycle
of opioid escalation and anxiety both for the physician and
patient [10].
Like methadone- and buprenorphine-maintained patients,
heroin-dependent patients have been shown to be signifi-
cantly hyperalgesic to cold-pressor pain in comparisons
with non-drug users [11]. It has been reported that pain-
free injury sites can temporarily become painful again when
stopping opioids, a phenomenon that has been recently
named withdrawal-associated injury-site pain [12]. Finally,
mini-opioid withdrawal, often associated with inappropriate
treatments, has been associated with OIH [13].
Acute opioid tolerance, defined as an increase in the
required opioid dose to maintain adequate analgesia, and
OIH, defined as a decreased pain threshold after long-
term opioid treatment, should be suspected with any unex-
plained pain report unassociated with disease progres-
sion. In particular, exposure to short-acting opioids, such as
Opioid-Induced Tolerance and Hyperalgesia
remifentanil, seems more likely to be responsible for post-
operative high pain scores, high morphine consumption, and
hypersensitivity to pain.
In this review the mechanisms of tolerance, including
drug-induced adaptations or allostatic changes at the cellu-
lar, circuitry, and system levels, that require increased opioid
drug doses to achieve the same effect, as well the progres-
sion to the state of hyper-excitation present with OIH are
described.
2 Mechanism of Tolerance
and Opioid‑Induced Hyperalgesia
2.1 The Descending System
The midbrain periaqueductal grey (PAG) is a key site of the
analgesic activity of opioids within the central nervous sys-
tem. Several studies have identified the postsynaptic adap-
tations induced by long-term opioid administration in PAG
and other brain regions [14, 15]. Opioids activate an anal-
gesic system within the PAG, disinhibiting γ-aminobutyric
acid (GABA)ergic activity by reducing the GABAergic inhi-
bition [16]. The GABAergic disinhibition is produced by
two independent mechanisms within the PAG: one is a direct
postsynaptic inhibition of GABAergic neurons; the second is
a presynaptic inhibition of release of GABA from nerve ter-
minals [16–18]. These mechanisms facilitate the activation
of the PAG descending analgesic system that projects via the
medulla to the dorsal horn. The postsynaptic mechanisms
have been focused on in different studies showing that long-
term opioid administration induces a reduction in postsyn-
aptic coupling of μ-opioid receptors to G-protein inwardly
rectifying ­K+ (GIRK) conductance and voltage-gated cal-
cium channels (VGCCs) within the PAG [19]. Moreover,
long-term opioid administration also reduces presynaptic
μ-opioid receptor inhibition by decreasing the size of the
vesicles available for action potential dependent release
[14]. This depletion leads to a reduction in μ-opioid receptor
presynaptic inhibition of GABAergic synaptic transmission.
Thus, long-term opioid administration reduces the presyn-
aptic opioid inhibition within GABAergic nerve terminals.
OIH is the increased sensitivity to pain following long-
term opioid treatment. Hyperalgesia may manifest as opi-
oid-induced tolerance since increased sensitivity to pain
would counteract the pain-relieving effects of opioids. The
increased activation of the descending pain pathway by opi-
oids produces neuroadaptations within the rostroventral-
medial medulla (RVM) that result in hyperalgesia [20].
Long-term administration of opioids produces an increase
in the number of active on-cells, which lowers the threshold
to noxious stimuli [21], believed to be responsible for OIH.
945
In the PAG–RVM connection, opioid tolerance is associated
with changes in a number of signaling cascades.
In contrast to the acute inhibitory effect of opioids on
cyclic adenosine monophosphate (cAMP) production, long-
term treatment upregulates cAMP. Direct activation of the
G-protein coupled opioid receptor induces the dissociation
of Gα and Gβγ subunits. The consequence of the dissociated
G-protein subunits is the inhibition of VGCCs and activation
of inward-rectifying potassium channels. In addition, down-
stream adenylate cyclase enzymes are inhibited, decreas-
ing cAMP levels and thus, the activation of the adenylyl
cyclase–cAMP–protein kinase A (PKA) pathway, which
results in a hyperpolarization and decreased neurotransmit-
ter release in the PAG, corresponding to anti-nociception
[22, 23]. Opioid binding also stimulates receptor phospho-
rylation by the G-protein–coupled receptor (GPCR) kinase
(GRK), which leads to β-arrestin recruitment to the receptor.
This results in receptor desensitization and internalization
(Fig. 1, left panel).
Long-term use of morphine produces adaptations that
contribute to opioid tolerance within all of these down-
stream signaling pathways. The sustained β-arrestin bind-
ing to the receptor leads to internalization, degradation, and
a decreased number of membrane receptors (Fig. 1, right
panel). Increased adenylate cyclase activity and PKA activa-
tion, activation of N-methyl-d-aspartate (NMDA) receptors,
and downregulation of glutamate receptors are all implicated
in attenuated analgesic effects, aggravated pain intensity,
increased tolerance, and OIH. In this regard, evidence is
available on the ability of NMDA receptor antagonists to
limit the development of opioid tolerance [24, 25].
The upregulation in cAMP seems to be caused by com-
pensatory changes in intracellular signaling, or an uncou-
pling of Gi-/Go-proteins from the receptor and a switch to
coupling with Gs-proteins [26]. The mechanisms underlying
receptor downregulation and tolerance may depend on the
specific agonist. Morphine does not readily recruit β-arrestin
or internalize the receptor, in contrast to high-efficacy ago-
nists such as fentanyl. Such differences in signaling suggest
that the mechanisms can be different. Morphine could use a
G-protein-dependent mechanism, while other opioids may
use a β-arrestin-dependent mechanism [27–30].
Opioid tolerance can be regulated by neuropeptides
within the descending pain pathway. Cholecystokinin (CCK)
within the PAG-RVM-dorsal horn pathway regulates mor-
phine tolerance [31, 32], as demonstrated by morphine toler-
ance being blocked with CCK receptor antagonists injected
into the PAG [31]. Injection of CCK in the RVM blocks opi-
oid activation of off-cells, which activate descending anti-
nociception, thus reducing the analgesic effects of morphine
[31, 33].
946 S. Mercadante et al.

Acute opioid treatment Chronic opioid treatment

Opioid
Opioid Desensized
receptor Ca2+ opioid receptor

P P
Gα Gβ K+ GRKP P GRKP P
Gγ
Adenylate
G protein β-arresn β-arresn
cyclase Recycling
Acvaon

Reduced
Internalizaon
effect
P
Receptor P
degradaon
Downstream Reduced
signaling downstream
signaling
Increased adenylate
cyclate levels,PKC
P PKA, and NMDA
P

Analgesic Tolerance and

effects insufficient analgesia Hyperalgesia

Fig. 1  Opioid receptor signaling and fate in response to acute and
chronic treatment. Direct activation of the G-protein coupled opioid
receptor induces the dissociation of Gα and Gβγ subunits. The conse-
quence of the dissociated G-protein subunits is the inhibition of volt-
age-gated calcium channels and activation of inward-rectifying potas-
sium channels. Downstream adenylate cyclase enzymes are inhibited,
decreasing cyclic adenosine monophosphate levels and, thus, the
activation of the AC-cyclic adenosine monophosphate (cAMP)-
protein kinase A (PKA) pathway. This results in a hyperpolarization
and decreased neurotransmitter release in the periaqueductal grey
(PAG), corresponding to anti-nociception. Opioid binding also stim-
ulates receptor phosphorylation by the G-protein-coupled receptor
kinase (GRK), which leads to β-arrestin recruitment to the receptor.
This results in receptor desensitization and internalization. Long-
term morphine administration produces adaptations that contribute
to opioid-tolerance within all these downstream signaling pathways.
The sustained β-arrestin binding to the receptor leads to internali-
zation, degradation, and a decreased membrane receptor number.
Increased adenylate cyclase activity and PKA activation, activation
of N-methyl-D-aspartate (NMDA) receptors, and downregulation of
glutamate receptors are all implicated in attenuated analgesic effects,
aggravated pain intensity, increased tolerance, and opioid-induced
hyperalgesia. PKC protein kinase C

2.2 Inflammation septic shock [36]. TLR-4 is expressed on microglia, and to

Increasing evidence indicates that the inflammatory response
is directly involved in opioid-induced tolerance and hyper-
algesia. Opioids have been shown to trigger innate immune
sensors on cells present at the neuroimmune interface, lead-
ing to the production/release of numerous pain mediators,
including cytokines, chemokines, prostaglandins, and reac-
tive oxygen species. This finally results in sensitization and
threshold lowering of neuronal firing. The repeated adminis-
tration of opioids activates the glia within the PAG and spi-
nal cord of the descending pain pathway, initiating a cascade
of signaling events [34, 36].
Of particular importance in the activation of the opioid-
induced inflammatory response is Toll-like receptor (TLR)-
4, the receptor that recognizes endotoxin and generates
a lesser degree on astrocytes, and has been implicated in
the development of opioid tolerance, allodynia, and OIH
[37–41]. In addition, in the spinal cord, TLR-4 is upregu-
lated after opioid treatment [42] and its upregulation is asso-
ciated with enhanced nociception in diverse pain models
[41].
Interaction of opioids with the TLR4 accessory molecule
MD2 initiates a cascade of intracellular events, including
activation of the acid sphingomyelinase with the generation
of ceramide (Fig. 2). Ceramide is crucial for the formation of
lipid rafts, molecular platforms that promote the assembly of
TLR4 receptor complex and receptor dimerization. Moreo-
ver, ceramide activates mitogen-activated protein kinase
(MAPK) pathways and a number of transcription factors,
leading to the upregulation of proinflammatory cytokine
Opioid-Induced Tolerance and Hyperalgesia
LPS
LPS binding protein LPS
Acid
sphingomyelinase
Ceramide
TLR4 lipid
NADPH Ra complex
oxidase
IRAK4
IRAK1
TRAF6
TAK1
IKKs
NF-κB ERK1/2
Inflammatory genes
Fig. 2  Toll-like receptor (TLR)-4 signaling cascade in response to
lipopolysaccharide (LPS) or opioid interaction. TLR signal transduc-
tion initially involves MyD88, TRAM, TIRAP, and/or TRIF adap-
tor proteins and the interleukin-1-receptor associated kinase (IRAK)
kinases. Interaction of opioids with the TLR4 accessory molecule
MD2 initiates a cascade of intracellular events including the activa-
tion of the acid sphingomyelinase with generation of ceramide that
is crucial for the assembly of TLR4 receptor complex and receptor
dimerization in the lipid rafts. In addition, ceramide activates nico-
tinamide adenine dinucleotide phosphate (NADPH) oxidase. TLR4
opioid engagement also activates the phosphatidylinositol 3-kinase
expression and cyclo-oxygenase (COX)-2 with increased
formation of prostaglandin E2 (PGE2), and enhanced gener-
ation of reactive oxygen and nitrogen species and peroxyni-
trite. Spinal peroxynitrite has been reported to be involved
in OIH in that SRI-110, which is a superoxide-sparing per-
oxynitrite decomposition catalyst, can prevent both analge-
sic tolerance and OIH by lowering the morphine-induced
upregulation of the proinflammatory cytokines (tumor
necrosis factor [TNF]-α, interleukin [IL]-1β, and IL-6) and
increasing that of the anti-inflammatory cytokines (IL-4 and
IL-10) [43]. Thus, removal of superoxides and peroxynitrites
by restoring spinal mitochondrial function may increase the
levels of anti-inflammatory mediators, improving opioid
performance
947
MD2
CD14
T T
I R
M R A T
y A M R
D P
I
8
8 F
RIP2
PI3K
MAPKs
Akt
Cell survival/death
JNK p38 Molity
(PI3K)/Akt pathway involved in the control of cell motility, sur-
vival, and apoptosis; p38 and extracellular signal-regulated kinase
(ERK) 1/2 mitogen-activated protein kinase (MAPK) and nuclear
factor (NF)-κB pathways regulating the expression of genes encod-
ing proinflammatory cytokines and chemokines; inducible nitric
oxide synthase (iNOS) and NADPH oxidase 2 (NOX2) leading to
generation of reactive nitrogen and oxygen species, respectively; and
cyclo-oxygenase (COX)-2 involved in prostaglandin synthesis. IKK
IκB kinase complex, JNK c-JUN N-terminal kinase, RIP2 receptor-
interacting protein 2, TAK1 transforming growth factor-β-activated
kinase-1, TRAF6 tumor necrosis factor receptor-associated factor 6
Of interest, ceramide is also the precursor of sphingosine-
1-phosphate (S1P) receptor 1 (SIP1), which binds to specific
GPCRs expressed on neurons, astrocytes, and microglia in
the spinal cord and dorsal root ganglion (DRG), thus sug-
gesting an emerging role of ceramide–S1P pathway in pain
[44]. Finally, ceramide may also be involved in apoptotic
neuronal cell death [45]. OIH has been correlated with cera-
mide upregulation in astrocytes and microglia and is pre-
vented by administration of ceramide inhibitors [46].
TLR4 opioid engagement also activates the phosphati-
dylinositol 3-kinase (PI3K)/AKT pathway involved in
the control of cell motility, survival, and apoptosis, and
the p38, extracellular signal-regulated kinase (ERK) 1/2
MAPK, and nuclear factor (NF)-κB pathways, regulating
948 S. Mercadante et al.

the expression of genes encoding proinflammatory cytokines 2.2.1 Inflammatory Cytokines

and chemokines as well as of nitric oxide synthase (NOS)
and nicotinamide adenine dinucleotide phosphate oxidase
(NOX)2, thus leading to generation of reactive nitrogen and
oxygen species, respectively [47], and being COX-2 involved
in prostaglandin synthesis [35, 48, 49].
Inhibition of TLR4-induced microglial activation and cer-
amide biosynthesis attenuates the development of opioid tol-
erance, thus suggesting a relevant role of this pathway in the
development of opioid tolerance [37]. Moreover, as TLR4
is directly activated by opioids, it is conceivable that opioid
antagonists can be used to block TLR4-mediated microglial
activation and production of inflammatory mediators [50].
The mechanisms underlying the alterations of neu-
ronal signaling involve glial inflammatory cytokines,
which increase the number and activate neuronal AMPA
(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
and NMDA receptors and downregulate the GABA receptors
as well as the astrocyte glutamate transporter 1 (GLT-1) and
L-glutamate/L-aspartate transporter that are considered to
be responsible for the synaptic glutamate uptake, as well as
the outward potassium currents [51]. All these mechanisms
result in a global increase in neuronal excitability, reduc-
ing the opioid-induced hyperpolarization of µ-containing
GABAergic neurons [35, 52].
Among the inflammatory cytokines, a pivotal role in opioid-
induced neuroinflammation and development of tolerance is
played by TNF-α, which initiates the cascade of inflamma-
tory cytokines, i.e., IL-6 and IL-1β. Intrathecal administra-
tion of morphine results in increased TNF-α expression in
the spinal cord, and TNF levels further increase upon long-
term opioid treatment. Inhibition of spinal TNF receptor
signaling blocks the release of IL-6 and IL-1β, and treatment
with immunomodulatory drugs such as ibudilast (AV411)
and minocycline, which can impair, block, and even reverse
opioid tolerance, results in decreased TNF expression levels
[53].
There is also evidence that a combination of IL-1, TNF-
α, and IL-6 blockers [40] prevent OIH as well as the IL-1
receptor antagonist IL-1ra [54, 55] and the anti-inflamma-
tory cytokine IL-10 [54]. Finally, TNF-α and IL-1β were
found to activate high-frequency stimulation-induced hyper-
algesia and synaptic long-term potentiation (LTP) by the
involvement of their receptors on glial cells [56].
Together, these studies indicate a clear link between
cytokines, tolerance, and OIH.

Fig. 3  Functional interaction Chemokine

between chemokine receptors
and opioid receptors. Acute Chemokine Opioid Opioid
(short-term) and chronic (long- receptor receptor
term) opioid treatment may
involve chemokine signaling
pathways. Chemokine bind-
ing to its receptors results in
heterologous desensitization of
opioid receptors by Src family
kinase (SFK) activation, leading Acute opioid Chronic opioid
to the loss of opioid-induced
analgesia. Long-term opioid
treatment induces extracellular SFK pathway ERK pathways
signal-regulated kinase (ERK)
activation, which decreases
the nociceptive threshold and Heterologous Decreased
results in morphine-induced desensizaon
hyperalgesia and apparent loss
nocicepve threshold
of opioid-induced analgesia.
SFK activation may also cause
pain hypersensitivity through Desensizaon of Opioid-induced
a direct link with the ERK opioid receptors hyperalgesia
pathway

Loss of opioid-
induced analgesia
Opioid-Induced Tolerance and Hyperalgesia
2.2.2 Chemokines
Chemokines, which are mainly implicated in the control of
leukocyte trafficking, are also involved in OIH and tolerance
[57]. Functional interactions between chemokine receptors
and opioid receptors as well as their role in pain modula-
tion have been described [57] (Fig. 3). Opioid receptors and
chemokine receptors are often present together in the same
microenvironments and co-localize.
In the process of pain enhancement, chemokines are
secreted by the primary afferent terminal, where they act in
an autocrine and paracrine manner to induce the release of
calcitonin gene-related peptide (CGRP), substance P (SP)
and glutamate. The released chemokines also participate
in the sensitization of second-order neurons in the dorsal
spinal cord.
Because of the heterologous desensitization, a num-
ber of chemokines have been reported to desensitize the
µ-opioid receptor [58]. Morphine analgesia has been shown
to decrease in response to chemokine infusion or chemokine
receptor engagement [59], whereas it can be improved by
treatment with anti-chemokine receptor-neutralizing anti-
body or chemokine receptor antagonists [60]. In accordance
with this, the development of analgesic tolerance or OIH
[54] can be limited by treatment with antibodies directed
against chemokines or chemokine receptors [60, 61].
2.3 Purinergic Signaling
Several findings indicate that purinergic signaling can also
contribute to opioid tolerance. Morphine engagement of
the µ receptor results in upregulation of P2X4 receptor
(P2X4R) and P2X7 receptor (P2X7R) on microglia [62,
63], and genetic and pharmacological blockade of these
receptors attenuates tolerance [63–65]. Moreover, P2X4R
stimulated microglial release of the brain-derived neuro-
trophic factor (BDNF) [66], which induces disinhibition of
second-order nociceptive projection neurons in the spinal
dorsal horn [67, 68].
2.4 Neuropeptides
Several neuropeptides have been shown to display pro-
nociceptive activity that opposes anti-nociceptive action
of opioids. They have been proposed as part of a homeo-
static equilibrium in which exogenous administration of
opioids triggers the release of these peptides, which in turn
counteract the analgesic action of opioids, thus leading to
the development of hyperalgesia and analgesic tolerance
[69, 70].
In this regard, CCK, which is considered to be an
endogenous anti-opioid [71], neuropeptide FF (NPFF) and
949
orphanin FQ (OFQ)/nociceptin (NOP) as well as dynor-
phin [72–74] display pro-nociceptive activities that oppose
the anti-nociceptive action of opioids. The pharmacologi-
cal blockade of CCK2 receptors in the RVM results in a
blockage of the development of OIH [31]. In addition,
CCK receptor antagonists prevent the development of anti-
nociceptive tolerance to morphine [75].
Overall, these findings indicate that CCK activity in the
RVM may decrease the spinal analgesic effect of opioids
by favoring the descending pain facilitatory mechanism,
which results in an exacerbation of spinal nociceptive
sensitivity.
The activities of NPFF and OFQ/NOP are ambiguous.
They induce OIH-reversing morphine analgesia following
intracerebroventricular administration, while producing an
anti-nociceptive effect intrathecally [70, 76]. Indeed, sys-
temic administration of the NPFF receptor antagonist RF9
prevents the development of OIH and tolerance [76, 77].
Moreover, systemic administration of a selective antagonist
(J-113397) or the genetic deletion of NOP receptor or OFQ/
NOP precursor genes determines an increase of nocicep-
tive behavior in inflammatory pain models. Thus, the spinal
anti-nociceptive activity may prevail over supraspinal pro-
nociceptive effects [78, 79].
A role in pathological pain is also described for the neu-
ropeptides belonging to the tachykinin family [80]. The
tachykinin neurokinin (NK)1 receptor in the spinal cord
has been reported to be involved in glia activation during
OIH. In addition, glial cell activation induced by morphine
withdrawal and the consequent OIH are attenuated by the
tachykinin NK1 receptor antagonist L-732,138. Indeed,
a bivalent opioid agonist–NK1 antagonist prevented OIH
while not activating spinal glial cells. This observation sug-
gests that glia activation triggered by SP and OIH occurring
after prolonged morphine administration could be prevented
by concomitantly targeting opioid and NK1 receptors [81].
2.5 Epigenetics
The persistent nature of pain suggests that the epigenetic
machinery may be a critical factor driving chronic pain.
Indeed, epigenetic processes, comprising DNA methyla-
tion, chromatin remodeling, and non-coding RNA, have
been increasingly implicated in the development of OIH,
dependence, and tolerance.
Thus, administration of a histone acetyltransferase inhibi-
tor with morphine significantly reduced development of
opioid-induced mechanical allodynia, thermal hyperalge-
sia, tolerance, and physical dependence. Conversely, the
histone deacetylase inhibitor suberoylanilide hydroxamic
acid (SAHA) enhanced these responses, suggesting that the
balance of histone acetyltransferase versus histone deacety-
lase might regulate these morphine-induced changes [82].
950
In addition, DNA methylation is involved in the epi-
genetic regulation of pain. Opioid users exhibit increased
methylation of the opioid receptor promoter gene, thus
decreasing its transcription [83]. Moreover, opioids may
inhibit the gene demethylation of opioid receptors [84],
and the epigenetic regulation of the µ-opioid receptor gene
(OPRM1) has been also found to contribute to opioid toler-
ance in cancer patients [85].
Conversely, demethylation regulation has been implicated
in the increased expression of the BDNF in DRG neurons
following repeated administration of morphine leading to
OIH [86].
Recent evidence also indicates a role for microRNAs
(miRs) in regulating the actions of opioid drugs through the
opioid receptors. Thus, the let-7 family of miRs has been
found to be a critical regulator of receptor function in opioid
tolerance [87, 88]. A potential link between receptor expres-
sion and morphine treatment at the post-transcriptional level
in which miRNA23b is involved has been reported [89].
Thus, there are complex mechanisms able to induce
tolerance and OIH. However, the interaction of these
mechanisms, including the descending system, inflamma-
tion, purinergic signaling, neuropeptides, and epigenetics,
remains to be ascertained.
3 Therapeutic Strategies
A major dilemma is faced by clinicians in differentiating
OIH from tolerance. This differential diagnosis is challeng-
ing but necessary, as the treatment may be different. Making
this even more complicated is the need to distinguish among
OIH, progression of the disease, clinical exacerbation of pre-
existing pain, and the myriad of social and psychological
factors implicated in pain expression. From a clinical per-
spective, OIH is characterized by a diffuse and less definite
pain, often extending to other areas of distribution than the
pre-existing pain. OIH exacerbates a pre-existing painful
condition above previous pain levels. When a pre-existing
pain is undertreated or, in the case of tolerance, an increase
in the opioid dose is prescribed, this generally produces a
reduction of pain. Opioid tolerance can be overcome with
a dose increase of the opioid previously used. Generally, a
30–50% dose increase produces the same level of previous
analgesia. With OIH, pain often worsens with an increase
in opioid dose. Rapid opioid escalation without reporting
any benefit should be suggestive of the development of OIH.
Thus, when the intervals between these dose increases
shorten or dose escalation becomes more rapid, it is likely
that the opioid is going to lose its efficacy or is produc-
ing a state of excitation. In these cases, the patient has to
be weaned off the high dose of opioids. This decrease in
opioid dose may lead to a transient increase in pain or mild
S. Mercadante et al.
withdrawal symptoms, particularly if discontinuation is
too rapid. OIH may disappear only when a critical level of
opioid dose is reached. At the same time the previous pain
condition may still remain untreated and efforts should be
made to provide analgesia [90].
Various strategies may be helpful in this critical condi-
tion, such as providing extra-opioid analgesia using drugs
that may produce independent analgesic effects. However,
given the extreme conditions of high levels of tolerance or
OIH, it is difficult to find specific evidence regarding this and
no controlled study has ever assessed specific treatments.
Thus, a tailored treatment provided by skilled personnel,
in accordance with the individual condition, is mandatory.
Among the mechanisms involving tolerance and OIH,
it has been reported, as noted earlier, that the descending
system is of paramount importance. Drugs that act by rein-
forcing the inhibitory descending system may be beneficial
in such a context. Other than improving depression and
enhancing sleep, antidepressants may provide decreases in
perception of pain. These analgesic effects of antidepressant
drugs are not directly related to their antidepressant activity.
Their efficacy has been established in many painful condi-
tions and antidepressant drugs are commonly given to cancer
patients, particularly in the presence of a prevalent neuro-
pathic pain component [91]. However, this group of drugs
results in some common adverse effects, including antimus-
carinic effects, such as dry mouth, impaired visual accom-
modation, urinary retention, and constipation, antihistaminic
effects, such as drowsiness, and sympatholytic effects, such
as orthostatic hypotension. Alternative tricyclics with a
more noradrenergic activity, such as duloxetine, are often
preferred in patients predisposed to sedative, anticholinergic,
or hypotensive effects.
Sodium channel-blocking agents may act both centrally
and peripherally to reduce ectopic impulse generation and
the activity of hyperactive wide dynamic range neurons
in the dorsal horn. It has been suggested that changes
in ion channel activity are determinant in the molecular
mechanism of neuropathic pain. Systemic local anesthet-
ics, carbamazepine, phenytoin, and open sodium channel
blockers may be useful in states of neuronal excitation.
These agents principally act through an inhibition of
sodium channel activity in hyperactive and depolarized
nerves without interfering with normal sensory function.
This group of drugs also have some activity on presynaptic
calcium channels and postsynaptic receptors, and conse-
quently on the opioid system [92].
Anticonvulsant agents, such as gabapentin, pregabalin,
carbamazepine, phenytoin, valproate, and clonazepam, have
been reported to relieve pain in peripheral and central neuro-
pathic pain conditions, although contradictory results have
been reported. They also inhibit NMDA receptors and also
possess other activities, including sodium channel blockade
Opioid-Induced Tolerance and Hyperalgesia
for some. Evidence that gabapentin is analgesic is strong
and, combined with a favorable safety profile, has encour-
aged widespread use of this drug [91], although the real
advantages in extreme conditions of OIH have never been
investigated.
Anti-inflammatory drugs, both steroidal and non-steroi-
dal, may occasionally provide additional analgesia on top of
opioid analgesia with different mechanisms and may avoid
opioid dose escalation. These drugs could reduce cancer
pain by decreasing peritumoral edema or inhibiting the pro-
duction and activity of many mediators of peripheral inflam-
mation [93].
α2-Adrenoceptor agonists are analgesic drugs that can
synergize when coadministered with opioids. These supra-
additive interactions are potentially clinically beneficial.
The spinal cord is an important site of action of synergistic
interactions. Synergistic interactions between opioid and α2-
adrenoceptor agonists could be mediated by either intercel-
lular or intracellular mechanisms, depending on the location
of the receptors involved. In addition, α2A-adrenoceptors are
also expressed on descending noradrenergic axon termi-
nals, where they act as autoreceptors to inhibit noradrena-
line release. Opioid receptors are located in both primary
afferent neurons and spinal cord neurons receiving input
from primary afferents. The α2C-adrenoceptors are known
to be located primarily on spinal cord interneurons and to
a much lesser degree on incoming primary afferents. The
synergistic interaction would be due to coincident inhibi-
tion of two neurons in series in the same anatomical path-
way or via a retrograde feedback mechanism. The activa-
tion of both μ- and δ-opioid receptors can produce synergy
with α2-adrenoceptor agonists [94]. The clinical utility of
α2-adrenoceptor agonists during opioid dose reduction in
patients with OIH has been recently reported to contribute
to the recovery of normal nociceptive and anti-nociceptive
response [95]. Additional studies are necessary to fully char-
acterize the impact of opioid–adrenoceptor agonist coad-
ministration on analgesia versus undesired adverse effects
in the clinical setting.
According to the developing understanding of neuroplas-
ticity observed with the development of tolerance and OIH,
the use of agents that block the activity of NMDA receptors
may provide an option for the treatment of patients receiv-
ing high doses of opioids who lose their analgesia. NMDA
antagonists may have direct analgesic effects or reverse
opioid tolerance. Ketamine is a non-competitive NMDA
receptor antagonist that exerts its primary effect when the
NMDA receptor-controlled ion channel has been opened by
a nociceptive barrage. Therefore, ketamine produces only
a weak analgesic effect on acute pain but may significantly
influence the central hyperexcitability and ‘wind-up’ phe-
nomena in spinal cord neurons that presumably participate in
the development of opioid tolerance and OIH [96]. A burst
951
of ketamine and midazolam at low doses may reverse an
unfavorable opioid response, reduce the level of tolerance,
and assist the opioid switching [97].
Several studies have reported that some opioids tend to
produce less tolerance, and possibly OIH, than others. This
property probably relies on different receptor activities,
exerted, for example, by lipophilic drugs such as fentanyl,
methadone, and buprenorphine, in comparison with mor-
phine [98–101].
This is the basis for the concept of opioid switching. In
fact, the most well-known method to counteract the devel-
opment of tolerance or OIH is the discontinuation of the
offending opioid whose use had been the origin of these
molecular processes [102]. As patients need analgesics for
their pain, another opioid may provide a better analgesia
with a lower intensity of adverse effects. In this sense, hyper-
algesia can be considered a sign of neurotoxicity, which is
an adverse effect. In the clinical setting, sequential thera-
peutic trials with different opioids have claimed to improve
the balance between analgesia and adverse effects in condi-
tions where this balance is unfavourable [103]. The substi-
tution of an opioid for a previous one in order to improve
the clinical response has largely been reported as opioid
switching. Opioid switching has been reported to produce
a clinical improvement in a large number of patients with
chronic cancer pain presenting a poor response to one opioid
[104–106]. This observation, which implies the presence of
incomplete cross-tolerance among opioids, has contributed
to the conclusion that the µ-opioid analgesics differ from one
another, contradicting the concept of a uniform category of
µ-receptor opioid agonists similar to morphine in respect to
their mechanism of action. The molecular mechanisms, as
previously reported, may revert and a second opioid may
find a different receptor state, thus diminishing the state of
hyperexcitation [102].
The most important problem raised in the opioid
switching literature is the conversion ratio among opi-
oids in patients presenting a poor opioid response, with
an unfavourable balance between analgesia and adverse
effects. Several studies in the last decade have suggested
that opioids may exert different receptor activities. The
differences in equianalgesic potencies from naïve to highly
tolerant patients can be quite profound [107]. Moreover,
there is no evidence that a specific drug will have more
chance of success when switching from one opioid to
another [107]. It is commonly suggested that the doses
of the different opioids be converted using oral morphine
equivalents tables and then reducing the doses by 50% to
meet the possible asymmetric tolerance between opioids
[108, 109]. With methadone, the doses should be changed
according to the doses of the previous opioids: the higher
the dose, the higher the conversion ratio, and the lower the
dose of methadone. This approach has been suggested after
952
a series of studies that demonstrated that there is a pro-
portional inverse ratio with the doses of hydromorphone
and morphine, given before switching to methadone.
This statement is explained by the peculiar pharmacody-
namic and pharmacokinetic characteristics of methadone,
including a weak anti-NMDA activity. Continuous use of
methadone, titrating by one-third of the calculated dose for
3 days has been suggested [110]. An alternative proposal
is an initial fixed ratio of 1:5 with oral morphine equiva-
lents [111, 112]. Methadone doses should be changed in
the subsequent days according to the clinical response.
This approach is based on the individual response, due to
a huge number of unpredictable factors, requiring clini-
cal flexibility, and provides rapid achievement of clinical
stabilization. However, in patients receiving high doses
of opioids, switching requires an appropriate setting and
monitoring. In particular, in patients suspected to have
developed OIH, the conversion ratio should be more cau-
tious. Alternately, in such circumstances, methadone can
be given as needed.
Despite the favourable effects reported with opioid
switching, the data are based on open studies, most of
which are retrospective or small case series. Unfortunately,
in complex pain conditions it is quite difficult to conduct ran-
domized controlled studies, and a formal approach according
to evidence-based medicine is unlikely.
4 Conclusion
Any treatment aimed to reduce opioid consumption may be
indicated in where opioid tolerance of OIH exist. Interven-
tional techniques able to decrease the pain input may allow
a decrease in opioid dose, thus reverting the mechanisms
producing tolerance or OIH. Intrathecal therapy with local
anesthetics and a sympathetic block are the most common
techniques utilized in these circumstances [113, 114].
Compliance with Ethical Standards
Funding No funding was received for this article.
Conflicts of interest Sebastiano Mercadante, Edoardo Arcuri, and
Angela Santoni have no conflicts of interest to declare related to this
article.
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