US Pharm. 2012;37(5):HS-2-HS-7.
Pain is the most common reason that people seek medical attention.1
A recent study estimates that pain affects tens of millions of
Americans and costs the United States $635 billion annually because of
increased consumption of medical care and indirect costs from missed
workdays and loss of productivity.2 Management of chronic
pain with medications such as opioids is a common strategy, but chronic
pain can persist or worsen despite aggressive opioid therapy. This
article aims to shed light on the phenomenon of opioids that are
prescribed to treat pain but cause new or paradoxically worsening pain.
This condition is called opioid-induced hyperalgesia (OIH). OIH may be more formally defined as increased nociceptive sensitization caused by exposure to opioids.3
OIH differs distinctly from tolerance, addiction, dependence, and
disease progression. The clinical prevalence of OIH is unknown.4
Diagnosis and Presentation
One of the chief problems in properly diagnosing OIH is the
condition’s close resemblance to opioid tolerance. Tolerance and OIH
share the characteristic of reduced analgesic response to the opioid
dose, and they likely share many of the same cellular mechanisms.5
Tolerance can be overcome by increasing the opioid dose, whereas the
same increase in a patient with OIH results in worsened pain.4
Additionally, tolerance tends to develop slowly over time, whereas the
increased pain resulting from opioid treatment in the OIH patient occurs
relatively quickly. Often, OIH differs from tolerance in that the pain
intensity is stronger than initially reported.6
Undertreated pain is another possibility that should be ruled out. If
opioid therapy is suboptimal, increasing the dose should lead to pain
relief; if OIH is present, the opposite should be true. For an accurate
diagnosis of OIH, the pain must resolve once treatment with the
offending opioid is discontinued.6 To complicate matters further, hyperalgesia resulting from opioid withdrawal is a well-documented phenomenon.7
As such, pain resolution from opioid discontinuation in OIH will not be
immediate and will require patience. This poses its own challenges for
both clinician and patient.
OIH tends to present with other distinct characteristics (TABLE 1).
Pain associated with OIH tends to be more diffuse and of lesser
quality, and noxious stimuli tend to be more painful that would normally
be expected. In OIH, pain often manifests in areas extending beyond the
region of injury or tissue damage. Pain can persist in OIH despite
removal of the original source of pain or healing of the damaged tissue.
In OIH, as opioid treatment progresses, the pain may give the illusion
of getting worse than originally reported despite time, rest, and other
measures that would normally allow for a clinically relevant amount of
healing.5 Additionally, allodynia has been demonstrated in a number of human and animal studies of OIH.8
There are a number of theories regarding the cause of OIH. The theory
that has been the most researched and is currently receiving the most
attention is the neuroexcitatory model. It is believed that certain
opioids and their metabolites agonize the N-methyl-D-aspartate
(NMDA) receptor. Activation of the NMDA receptor causes an influx of
calcium that greatly enhances the excitability of the neuron. When the
NMDA receptor and corresponding neurons are more active, they can more
readily transmit painful impulses initiated by circulating substance P
or other noxious stimuli. Glutamate is the primary endogenous agonist of
the NDMA receptor.9
Supporting this theory of pronociception modulated by NMDA receptor
activation are studies showing relief of OIH after administration of
NMDA receptor antagonists. These antagonists noncompetitively bind to
the phencyclidine site on the NMDA channel and block the influx of
calcium that would occur when the receptor binds glutamate or another
agonist.10 Animal and human studies have demonstrated that
subjects with OIH who were administered ketamine, an NMDA receptor
antagonist, scored better during controlled pain-stimulus testing. In
one study, rats were given intrathecal morphine injections for several
days until they displayed OIH that was sensitive to heat. Administration
of dizocilpine, an NMDA inhibitor, was effective in at least partially
reversing thermal hyperalgesia.5 Other NMDA receptor
antagonists, such as dextromethorphan, have demonstrated some evidence
of relieving hyperalgesic states through inhibition at the NMDA
Opioids, such as codeine, hydromorphone, and morphine, undergo a
number of biotransformations as part of the normal metabolic process.
Codeine is metabolized into morphine by the CYP2D6 enzyme. Morphine is
metabolized into a number of molecules, but it is metabolized primarily
through glucuronidation into morphine-3-glucuronide (M3G) and, to a
lesser extent, morphine-6-glucuronide (M6G) (FIGURE 1).11
M6G is a therapeutically important metabolite. It has mu receptor
binding affinity similar to that of morphine and is capable of producing
analgesia, respiratory depression, and other effects similar to those
of morphine. M3G, however, is not an agonist at the mu receptor, and it
has little affinity for the mu receptor compared with morphine. Unlike
morphine, M6G, and other opioids, M3G is an NMDA agonist. Through
glucuronidation, M3G is converted at a rate about six times greater than
that of M6G.12 Other opioids have been implicated in having NMDA agonist activity and paradoxical neuroexcitatory effects.6
Supporting the theory that OIH is caused by activity of receptors
besides the mu opioid receptor is evidence that OIH is not alleviated by
administration of an opioid antagonist (e.g., naloxone). In patients
experiencing OIH while on high-dose opioid therapy, administration of
naloxone caused a worsening of pain.13 By displacing the
opioid from the mu receptor, naloxone prevented the opioid from
providing what analgesia was possible through mu receptor activation,
while concurrently the hyperalgesia now remained unchallenged.14
Dynorphin may also be involved in the development of OIH.15
Dynorphin is an endogenous opioid peptide that binds primarily to the
kappa opioid receptor and, to a lesser extent, the mu opioid and NMDA
receptors. It is believed that dynorphin’s agonism of the kappa opioid
receptor and NMDA receptor has a role in the pronociception of OIH
despite the presence of pure mu receptor agonists. Studies have shown
that reversal of dynorphin can restore the analgesic effects of morphine
when subjects are given a dynorphin antiserum. Furthermore, dynorphin
is known to increase during prolonged opioid administration. Dynorphin
also causes the release of excitatory neuropeptides within different
locations in the central nervous system.
Once the diagnosis of OIH has been made, there are a number of
treatment options from which to carefully choose. Provided that the
initial painful injury or tissue damage has resolved and the pain
persists in spite of—and because of—opioid treatment, the most
straightforward approach is to discontinue the offending opioid. This
should be done gradually to minimize adverse withdrawal effects. It
should be noted that hyperalgesia may likely worsen early in the
discontinuation process.16 This presents a challenging
ethical situation in which the clinician may have difficulty convincing
the patient that the medication prescribed to treat pain may have been
causing or worsening the pain and that the pain may get worse still
before it ultimately resolves.17
If legitimate pain persists and some amount of analgesia with opioids
is required, other strategies beyond total opioid discontinuation
should be explored. Patients experiencing OIH may obtain relief by
reducing the opioid dose.4 There are reports of patients
finding an acceptable balance of analgesia and relief from hyperalgesia
upon opioid dose reduction.
Switching from one structural class of opioids to another has been an
effective option for mitigating OIH in some studies. Studies to date
have demonstrated that OIH is more strongly associated with opioids from
the phenanthrene class (TABLE 2).4 Titration of the
phenanthrene opioid and conversion to another may provide resolution of
OIH. Codeine, hydromorphone, morphine, and structurally similar opioids
undergo glucuronidation as part of their metabolism. Avoidance of an
NMDA receptor–activating glucuronide metabolite is possible by switching
to an opioid that is structurally unique, such as fentanyl. At this writing, OIH has not been demonstrated in trials involving oxymorphone.4
Supplementing opioid therapy with a cyclo-oxygenase 2 (COX-2)
inhibitor is another strategy that has some support. By reducing
prostaglandin synthesis, COX-2 inhibitors can decrease the sensitization
of pronociceptive neurons. Nonsteroidal anti-inflammatory drugs
(NSAIDs) and COX-2 inhibitors appear to have analgesic effects
independent of their ability to suppress prostaglandin synthesis
peripherally.9 COX-2 inhibitors also have demonstrated the
ability to antagonize the NMDA receptor. Centrally, NSAIDs are capable
of antagonizing the NMDA receptor by blocking glutamate, substance P,
and other excitatory amino acids. Independent of this, NMDA receptor
activation can upregulate COX-2 expression.18
Given the attention the NMDA receptor has received for its role in
OIH, antagonizing this receptor would seem to be a reasonable treatment
strategy. Ketamine has been much researched, but its adverse effects can
be severe. While it antagonizes NMDA and provides an anesthetic effect
that would promote analgesia, side effects are common, diverse, and
severe.19 These effects include tachyarrhythmia,
hypertension, cognitive impairments, and psychomimetic reactions,
including mood changes, vivid dreams, delirium, hallucinations, and
sedation. Ketamine is effective in reversing hyperalgesia and augmenting
the effects of opioids in patients receiving large doses, but its
adverse effects prevent it from being a viable treatment option.
Dextromethorphan is another NMDA receptor antagonist that has been
investigated for the treatment of OIH. A combination product containing a
1:1 mixture of morphine and dextromethorphan has been studied.20
Studies failed to demonstrate that combination therapy could achieve
superior analgesia compared with morphine alone. Similar therapy
failures occurred in a study that used a 2:1 mixture of the same agents.
The studies have been criticized for having an insufficient amount of
dextromethorphan to adequately antagonize the NMDA receptor.21
What remains unknown is the dose of dextromethorphan necessary to
either augment an opioid’s analgesia or prevent the OIH caused by NMDA
Methadone is an opioid with unique qualities that make it a
compelling option for treating pain in the patient with OIH. In addition
to its analgesic effects through binding to the mu opioid receptor,
methadone is a weak NMDA receptor antagonist.4 It has been
reported that the addition of even a low dose of methadone has been
effective for reducing hyperalgesia. In one case, the addition of
low-dose methadone (10 mg twice daily) improved reports of pain
markedly, with a reduction in total opioid dose of 40% to 50%.22
Switching from the offending opioid to methadone has been a popular
treatment strategy. Tramadol and meperidine also have some NMDA receptor
Another treatment modality that has some potential for treating OIH is buprenorphine.23,24 Buprenorphine is a partial opioid agonist at the mu receptor and also has kappa receptor antagonist activity.4
Dynorphin, a kappa receptor agonist, is known to increase during
treatment with opioids. Activation of the kappa receptor largely
antagonizes the mu receptor–mediated effects of opioids.25 The clinical utility of buprenorphine in treating OIH has yet to be fully explained.
Conclusion: Looking Forward
Much work remains to be done before it can be declared that OIH is
understood. The exact cellular mechanism and signaling pathways
responsible for this phenomenon are not defined. To complicate this,
there are conflicting reports as to whether specific components play a
key role, or any role whatsoever. The bulk of research on elucidating
the pathophysiology of OIH has involved the animal model. This has some
value, but information from the human model is scarce.
A weak understanding of the cause of a condition generates an
uncertain armamentarium of treatment options. The best strategy
available is total discontinuation of the problematic opioid, but this
is of little use to the patient who requires opioid-type pain relief.
Several other treatment modalities have been explored, but all of them
would benefit from further study. The majority of studies done in humans
involve perisurgical patients, recovering drug addicts, and
experimental pain models. These studies are not without value, but these
populations do not mirror the chronic pain population. Other
limitations of available treatment options include lackluster results,
excessive toxicity despite moderate success, and small studies producing
At this writing, a number of clinical studies using the NMDA receptor antagonist memantine to treat OIH are ongoing or planned.26
Still, there are conflicting reports as to the exact role of NMDA
receptors in OIH. Further research must be done to determine the key
responsible receptors and mechanisms present in OIH. Expanding the
sample size of studies will help support conclusions already made about
which treatment agents are responsible for OIH and effective for
treating it. Conducting studies that focus on chronic pain, rather than
models of acute pain, can bring clinically relevant information to the
Chapman and colleagues have raised specific questions that must be
answered before diagnosis of OIH and effective treatment can be
delivered.27 What are the relationships of opioid dose and
duration to OIH? With what type of pain, or in what type of patient, is
OIH more apt to develop? These are the questions that must guide future
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