Opioid-Induced Hyperalgesia (OIH)
Opioid-Induced Hyperalgesia (OIH) is defined as “an increased response to a painful stimulus caused by exposure to opioids.” It is the subject of current debate regarding it’s clinical significance.
Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful.
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Opioid Induced Hyperalgesa (OIH)
Chronic pain in the absence of opioids is known to induce changes in the nervous system that result in hyperalgesia. These changes include changes within the dorsal horn of the spinal cord and inhibition of the pain-suppressing descending pathways from the brain to the spinal cord. Although these changes appear to be independent of the changes postulated with OIH, there does appear to be the potential for at least some overlap in the mechanisms.
In the current climate of political turmoil regarding the prescribing of opioids, OIH is often presented as an argument against the use of opioids for chronic pain. At this point in history, the research to support clinically significant OIH in the usual prescribing patterns of opioids for chronic pain is weak. Most of the human studies of OIH involve patients taking methadone for addiction and these studies are far from clear with respect to clinical relevance. Even in studies of patients taking methadone for pain it hass suggested that the hyperalgesia observed with methadone therapy may be a result of the transient withdrawal that results from a dosing schedule that outlasts its short analgesic half- life.
Most OIH studies are animal studies and the extrapolation of these findings to humans in a relevant application to opioid pain management is simply untenable at this time. While there are some human studies that indicate some increased sensitivity to cold or heat pain, other studies find no increased sensitivity. In fact, one of the best, large studies published in 2005 evaluating OIH in chronic pain patients treated with opioids and non-opioids revealed no difference in pain sensitivity between opioid and non-opioid managed patients. This lack of difference also held between high-potent and low-potent opioids as well as high-doses and low-doses of opioids.
In the study of OIH it has become evident that, while they are separate entities, there is overlap between OIH and opioid tolerance with regard to mechanisms and clinical manifestations. Furthermore, it has also been established that most types of chronic pain leads to central sensitivity, a condition associated with increased sensitivity to both painful (hyperalgesia) and non-painful (allodynia) stimuli in the absence of opioid management. By design, many of the currently published studies suggesting opioid-induced hyperalgesia in chronic pain patients do not, and likely cannot distinguish between “opioid-induced” and “chronic pain-induced” hyperalgesia.
In addition to OIH, another commonly experienced opioid-related pain experience is Withdrawal-Induced Hyperalgesia (WIH). When a person abruptly withdraws from opioid use, prescription or illicit, pain is experienced more severely. In addition, it has been found that many people may experience re-activation of a pain related to a remote injury or trauma that had previously resolved prior to initiating opioid therapy, even injuries from childhood (Withdrawal-Induced Injury Site Pain or WIISP). Sensitivity in areas of previous trauma can also be different from the original pain.
See Withdrawal-Induced Hyperalgesia (WIH)
Risk for OIH
Understanding what is known about OIH may lead to steps one can take to reduce the risk of OIH as a measure of prevention. Administration of large doses of opioids for a prolonged period seems to be associated with a higher incidence of OIH but it can also be seen when opioids are administered for a short period as evidenced with peri-operative use of fentanyl and post-operative pain. OIH can develop differently for different types of pain and vary according to the different stimuli (mechanical, cold, heat, electrical). OIH is also observed after discontinuation of the opioid after prolonged use and likely correlates in severity with . Opioid-dependent patients show sensitivity to cold, but not to electrical and mechanical stimuli. Increased sensitivity to cold and heat without affecting pressure sensitivity can be observed. OIH is reversible but it may requires a long period of abstinence.
Manifestations of OIH
There are different manifestations of “Opioid Induced Hypersensitivity.” The increased pain triggered by OIH is more severe than the initial pain and it presents somewhat vaguely, being poorly characterized in terms of quality and poorly localized. The pain of OIH is widespread and in areas anatomically different from the original source of pain. Most importantly, OIH is characterized by the paradoxical development of increased pain with increasing doses of opioids rather than the expected reduction of pain. This pain can manifest as either hyperalgesia or allodynia, or both.
There is some evidence for OIH in post-operative pain with patients treated intra-operatively with fentanyl. Research has also looked at methadone maintenance patients who experienced increased pain after exposure to opioids in a “cold pressor” test. This test involves monitoring the subjective experience of pain while the subject immerses their arm in ice water while a blood pressure cuff is inflated to impair blood flow to the immersed arm. Sensitivity to cold pain is experimentally measured by the time it takes to induce pain. Subjects treated with opioids, in some studies, display a more rapid onset, or more severe pain. Some would extrapolate this to the argument that opioids induce hyperalgesia in clinical management of chronic pain but this extrapolation lacks literature support. One has to question the clinical relevance of a study of this nature but studies of this nature are often quoted as evidence for OIH as part of an anti-opioid stance for treating pain. The argument that opioids induce hyperalgesia with respect to heat, mechanical or electrical stimulation is also lacking clinically relevant evidence.
In clinical practice, significant OIH has been reported but appears to be rare and largely anecdotal. Furthermore, distinguishing OIH and it’s associated behavioral patterns of patients requesting increasing doses from addiction with increasing doses due to the development of tolerance to the euphoric aspects of the prescribed opioids requires further investigation.
OIH versus Opioid Tolerance
In opioid tolerance there is less clinical response to opioids so that to achieve the same benefit from the opioid, higher doses are required. This is the opposite to OIH in which higher doses of opioids increase pain and pain sensitivity. OIH and opioid tolerance are pharmacologically distinct phenomena but at times it may be initially difficult to distinguish between the two. Furthermore, both conditions may coexist and evidence that tolerance and hyperalgesia share several cellular mechanisms and some neurotransmitters and receptors systems, including dynorphin, protein kinase-C, NMDA receptors, nitric oxide synthase, heme oxigenase, and others exists.
See: Opioid Tolerance
Neurobiology of OIH
Multiple factors and mechanisms contribute for OIH, such as: changes in opioid receptors, NMDA receptors and intracellular messengers, spinal COX activation, release of excitatory amino acids and reduction of inhibitory neurotransmitters and activity of descending nerve pathways. Changes can be seen in the central and peripheral nervous system, with sensitization of pro-nociceptive (pro-pain) pathways. Cellular changes are seen in several anatomical sites, such as afferent neurons and spinal cord, glia, the brain, and descending nerve pathways. Changes can be seen in receptors and nerve channels, as well as peripheral and central sensitization.
See: Neurobiology of Pain
Mechanisms Related to Opioid Receptors
Opioid receptors are concentrated in peripheral nociceptive fibers (pain-detection nerves) that synapse centrally upon dorsal horn neurons in the spinal cord and in pathways descending from the brains (rostral ventral medial medulla) to the spinal cord. When opioids activate opioid receptors, a cascade of neurochemical events are triggered that ultimately reduce transmission of pain signals to the areas of the brain that perceive pain, resulting in analgesia (relief of pain).
Opioids appear to induce hyperalgesia by multiple proposed mechanisms. Chronic exposure to opioids is believed to reverse to some extent this cascade of events resulting in enhanced release of pain-inducing neurotransmitters that leads to increased pain perception. This mechanism may also explain opioid tolerance as it will counteract with the analgesic effects of opioids resulting in decreased effectiveness of opioids over time. If opioids are discontinued, this mechanism helps explain withdrawal-induced hyperalgesia as well.
Another proposed mechanism involves changes in the signaling in the descending neural pathways between the brain and spinal cord which function to suppress pain. Due to the concentration of opioid receptors in the brainstem that connect with the descending pathways, it is postulated that chronic exposure to opioids reduces the transmission of these pain-suppressive signals leading to increased sensitivity to pain. The activity of these descending pathways can be modified by gabapentin (Neurontin) and pregabalin (Lyrica), suggesting a possible clinical benefit with the use of these medications in reducing OIH.
Mechanisms Independent of the Opioid Receptors
Toll‐like Receptors (TLR)
Opioid receptor independent mechanisms of OIH also exist. Morphine‐3‐glucuronide (M3G), a liver metabolite (breakdown product) of morphine, increases neuronal excitability via Toll‐like receptors (TLR). Morphine activation of TLR4, concentrated in spinal microglia (immune-related cells in the nervous system), causes the release of inflammatory proteins (interleukin‐1, and tumor necrosis factor (TNF‐α), that result in neuroinflammation and increased pain. Toll‐like receptor antagonists have been identified as possible treatments for alleviation of glial sustained hyperalgesia.
Activation of NMDA receptors by glutamate is implicated in the mechanism of OIH. The increase in the release of glutamate in the dorsal horn of the spinal cord and the sustained increase in the response of NMDA receptors through protein kinase-C -mediated manganese removal, seem to be the main mechanisms implicated in OIH. NMDA receptors can be activated by opioids.
Activation of COX-2 receptors in the spinal cord play a role in OIH and prostaglandins are involved in NMDA activity and the development of hyperalgesia. There are studies that suggest the benefit of the Cox-2 inhibitor, celecoxib (Celebrex), in suppressing the development of OIH.
ROS, Oxidative Stress and Mitochondrial Dysfunction
Animal studies have identified a role of reactive oxidative species (ROS), free radicals, in the development of neuropathic and inflammatory pain, hyperalgesia and central sensitization. The role of ROS species in the dorsal horn neurons including the superoxide free radical produced in mitochondria and superoxide dismutase, the antioxidant manufactured in mitochondria have been implicated in neuropathic pain, hyperalgesia and central sensitization.
Furthermore, mitochondrial dysfunction has also been identified as a likely contributor to neuropathic pain as well as the hyperalgesia, allodynia and central sensitization associated with fibromyalgia.
Based on this preliminary research, it would appear prudent to minimize oxidative stress as a means of reducing or reversing neuropathic pain, OIH and central sensitization as well possibly reducing risk for developing atherosclerosis or Alzheimer disease. Supplements including various antioxidants, NRF2 activators and nicotinamide riboside (NR) have growing evidence for their potential benefit in these conditions.
Epigenetics has been simply defined as the study of how genes are controlled by turning them on or off. More specifically, epigenetics is defined as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.” Animal studies have indicated that ther regulation of certain genes plays a role in processes leading to OIH.
Commonly studied epigenetic processes include the modification of histone proteins by acetylation, phosphorylation and methylation as well as the methylation of DNA, though many other epigenetic mechanisms exist as well. The acetylation of histone causes the relaxation of chromatin and, generally, the enhancement of transcription of genes in the relaxed regions. In other words, by chemically interacting with the chromosomal DNA of a gene, the gene is made accessible or not accessible to the RNA that builds proteins and other molecules directed by the gene.
The acetylation process is regulated by the balance of activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. Curcumin is known to inhibit the HAT enzyme and has been shown to suppress the development of OIH in mice studies. Curcumin, a potent antioxidant and NRF2 activator (see above), has also been shown to be affective for many pain-related conditions including arthritis. While the understanding of the clinical benefits of curcumin for OIH are still in the stage of pre-clinical animal studies, a role for epigenetic mechanisms in pain processing has been established including the transition of acute to chronic pain, neuropathic pain (including hyperalgesia and allodynia), visceral pain, central sensitivity and opioid analgesic tolerance.
Genetics and OIH
There may be a role for genetic variants to influence the development of OIH. There is growing evidence for the role of COMT genetics in the degree in which people are sensitive to pain and some hypothesize that COMT may also play a role in OIH (see Genetics – COMT). COMT is the enzyme that breaks down dopamine and noradrenaline, two neurotransmitters involved in many neural pathways and people have wide genetic-based variations in how fast these neurotransmitters are metabolized. Dr. Ehlenberger is preparing to start a study in the near future that will investigate possible associations between a person’s COMT activity, pain sensitivity and OIH.
Variants of the genes that express levels of function of the P‐glycoprotein transporter (the mechanism by which some opioids are transported out of the central nervous system) have been identified that predispose certain animals to hyperalgesia.
Treatment of OIH
OIH treatment is complex and requires a specific strategy which may vary from one patient to another. The management differs depending on how the OIH presents. When there is a clear pattern of increasing pain as the opioid dose increases, simply reducing the opioid dosing will improve the pain – both confirming the diagnosis as well as treating the condition.
A more subtle situation occurs when a patient on chronic opioid therapy (theoretically) slowly develops increasing OIH. While the evidence for this condition to be clinically relevant is weak, it should be considered when a patient on opioids begins to experience worse pain, especially if the pain worsens with increasing opioid doses instead of lessens and the increased pain extends to areas distant from the original focus of pain. Practically speaking, opioid reduction might induce withdrawal symptoms, which can include an increase in pain. That increase in pain will mask the clinical picture and make the differentiation more difficult.
An alternative approach would be to rotate to a different opioid, particularly one with NMDA antagonist activity such as levorphanol, methadone or buprenorphine. Studies support the benefits of rotation to methadone, a weak NMDA antagonist, in cases of OIH and the use of levorphanol, a strong NMDA antagonist, would be expected to offer even greater potential for benefit in OIH. Because there may be a role of the kappa opioid receptor activity in the development of OIH, it has also been suggested that buprenorphine, with kappa antagonist activity, may be beneficial in OIH.
Since the main proposed mechanism for OIH involves the NMDA receptors, there is some research to support the benefit of NMDA blockers such as ketamine (see also Compounded Topical medications), memantine and dextromethorphan in suppressing OIH.
Recent research showed that oral ketamine at low, slowly increasing doses may prove effective in neuropathic pain and would likely benefit OIH as well. Side effects with ketamine tend to be limiting, including hallucinations and dysphoric moods. Depending on the source of pain, there may be an argument for the use of topical ketamine which is not associated with systemic side effects.
Dextromethorphan (DM) may also be a treatment option although research to date suggests that doses of DM required to be effective are also associated with significant side effects including sedation.
MgSo4 (epsom salts) are thought to be an NMDA antagonist and may offer benefit, though no research appears to have looked at this.
Because buprenorphine, methadone and levorphanol are believed to provide NMDA blocking activity, they are recommended for pain as a means of reducing or reversing the development of OIH.
There is growing evidence that adding gabapentin (Neurontin), pregabalin (Lyrica) or even clonidine may be effective against OIH. Current research indicates that the gabapentinoids, gabapentin and pregabalin, have multiple mechanisms by which they reduce pain and some of these mechanisms suggest potential benefit in reducing OIH. In one study, gabapentin acted synergistically to prevent OIH when combined with ketamine.
There is some pre-clinical animal study evidence that ondansetron (Zofran), an anti-nausea medicine may be effective in reducing or preventing OIH, as well as reducing the development of opioid analgesic tolerance. Ondansetron has also been found clinically useful in reducing some of the symptoms of acute opioid withdrawal, including withdrawal-induced hyperalgesia (WIH) as well as the nausea.
Prevention of OIH
Given the potential role of oxidative stress and ROS such as superoxide, a potential means of preventing OIH lies in reducing oxidative stress through supplementing with antioxidants or, preferably, NRF2 activators. This approach is theoretical and not likely to be researched anytime soon, but it is an approach with practical arguments and the likelihood of additional health benefits as an affordable option.
OIH – Overviews
- The Evidence for Opioid-Induced Hyperalgesia Today – 2014
- Opioid-induced hyperalgesia – a review of epidemiology, mechanisms and management – 2012
- Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain – 2005
- Opioid-induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations – 2008
- A Comprehensive Review of Opioid-Induced Hyperalgesia – 2011
- Complexities of Opioid-Induced Hyperalgesia Poorly Understood – 2015
- Opioid-induced hyperalgesia – a clinical challenge – 2010
- Opioid-Induced Hyperalgesia – 2014 Medscape
- Opioid-induced hyperalgesia – What to do when it occurs? – 2012
- The Dilemma of Opioid-Induced Hyperalgesia and Tolerance in Chronic Opioid Therapy – 2013
- Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. 2008 – PubMed – NCBI
- Opioid induced hyperalgesia – clinical implications for the pain practitioner. – 2009
- Opioid-Induced Hyperalgesia – 2012
- Opioid-Induced_Hyperalgesia_OIH – 2010
- Hyperalgesia in Heroin Dependent Patients and the Effects of Opioid Substitution Therapy – 2012
OIH – Epigenetics
- Could targeting epigenetic processes relieve chronic pain states? – PubMed – NCBI
- Telomeres and epigenetics – Potential relevance to chronic pain – 2012
- Epigenetics of chronic pain after thoracic surgery. – PubMed – NCBI
OIH – Gabapentin
- The median effective dose of ketamine and gabapentin in opioid-induced hyperalgesia in rats: an isobolographic analysis of their interaction. – PubMed – NCBI
- Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin – 2015
- The Anti-Allodynic Gabapentinoids – Myths, Paradoxes, and Acute Effects – 2016
OIH – Ketamine
- The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. – PubMed – NCBI
- The median effective dose of ketamine and gabapentin in opioid-induced hyperalgesia in rats: an isobolographic analysis of their interaction. – PubMed – NCBI
- Promising Data With Ketamine in Chronic and Phantom Limb Pain – 2016
- Sublingual Ketamine in chronic pain : Service evaluation by examining over 200 patient years of data | Jaitly | Journal of Observational Pain Medicine – 2013
- Use of oral ketamine in chronic pain management – a review. – 2009
- Ketamine for Treatment-Resistant Unipolar Depression – 2012
OIH – Ondansetron
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