Opioid-induced hyperalgesia

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Opioid-induced hyperalgesia[1] (OIH) or opioid-induced abnormal pain sensitivity,[2] also called paradoxical hyperalgesia[3], is a phenomenon associated with the long-term use of opioids such as morphine[citation needed], hydrocodone[citation needed], oxycodone[citation needed], and methadone.[4][5] OIH is characterized as generalized pain, not necessarily confined to the affected site[6]. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia)[citation needed]. Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.[7]

Tolerance, another condition that can arise from prolonged exposure to opioids, can often be mistaken for opioid-induced hyperalgesia and vice versa, as the clinical presentation can appear similar. Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation to receive the same level of effect to treat pain, they are nevertheless caused by two distinct mechanisms.[8] The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance, opioid-induced hyperalgesia, or a combination of both. In tolerance, there is a lower sensitivity to opioids, which occurs via two major theories: decreased receptor activation (desensitization of antinociceptive mechanisms), and opioid receptor down-regulation (internalization of membrane receptors).[9] In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodyna.[10] Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence.[citation needed]

The phenomenon is common among palliative care patients following a too rapid escalation of opioid dosage.[11][12]


The pharmacology of opioids involves the substance binding to opioid receptors in the nervous system and other tissues. The three known and defined receptors are mu, kappa and delta, with many other receptors reported as well. These receptors are notable for binding opioids and eliciting an analgesic response, thus alleviating the sensation of pain. The mu opioid receptor is targeted most often by opioids to relieve pain.[13] Two of the most commonly used opioid antagonists at the mu receptor are naltrexone and naloxone.[14] The pharmacology for opioid-induced hyperalgesia is more complicated, and is believed to involve the activation of NMDA receptors and increased excitatory peptide neurotransmitters (such as cholecystokinin.)[15]


There is increasing evidence in support of genetics being a key factor in the development of OIH through its influence on both pain sensitivity and analgesic control. Current evidence indicates that the genetic influence stems from polymorphisms of the gene coding for the enzyme, Catechol-O-Methyltransferase (COMT). Its enzymatic activity varies depending on its three possible genotypes, which are seen as a single amino acid change from valine to methionine, resulting in significant variability in its activity. Degradation of the neurotransmitters, dopamine and noradrenaline, is approximately 4 fold greater when the amino acid presented is valine instead of methionine. This results in modulation of the dopaminergic and noradrenergic response at the synaptic level of neurons, which has been linked to having effects on memory function, anxiety, and pain sensitivity in comparison to individuals presenting as homozygous for valine alleles of this particular gene (COMTval158).[16]

A number of opioids undergo metabolism by cytochrome P450 enzymes in order to generate active metabolites. Only by generating these active metabolites can analgesic effects occur. One of the enzymes that is used to metabolize opioids including codeine, methadone, hydrocodone, and tramadol is CYP2D6. The level of expression of CYP2D6 can vary dramatically between different individuals. Individuals with low expression of CYP2D6 are designated as poor metabolizers while individuals with high expression of CYP2D6 are designated as ultra-rapid metabolizers. This information is important for healthcare professionals to know as it determines how much opioids a patient will need in order to achieve the desired analgesic effect. If given the same starting dose of codeine, a poor metabolizer will feel very little pain relief while an ultra-rapid metabolizer may feel a large reduction in pain. Conversely patients who are ultra-rapid metabolizers should be given minimal amounts of opioids such as tramadol in order to avoid respiratory depression. Information regarding a patient's CYP2D6 expression can be found by running a genomic test such as 23andMe. This information is also helpful to healthcare professionals so they may modify the dosing of other drugs that may have drug-drug interactions with opioids such as rifampin.[17]

Mechanism of action[edit]

The precise mechanisms underlying opioid-induced hyperalgesia are poorly understood. The sensitization of pronociceptive pathways in response to opioid treatment appears to involve several pathways. Research thus far has primarily implicated the abnormal activation of NMDA receptors in the CNS, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn.[18] One possible strategy for treating hyperalgesia involves blocking activation of these receptors with NMDAR antagonists such as ketamine, dextromethorphan, or methadone (which has NMDAR antagonist properties in addition to being an opioid analgesic). Human studies examining the benefit of combining opioid treatment with NMDAR antagonism have yielded mixed results, and few conclusions can be drawn until larger studies are conducted. Targeting the NMDA receptors in areas of potential pathology (such as the dorsal horn of the spinal cord) is a challenge considering their widespread presence throughout the spinal cord and brain, and the profound psychotomimetic side effects associated with known NMDAR antagonists may limit their clinical potential as adjuvants to the treatment of pain. Gliosis due to the TLR4 agonist effects of opioids has also been implicated in both hyperalgesia and tolerance.[citation needed]


Treatment of opioid tolerance and Opioid-Induced Hyperalgesia differs but it may be difficult to differentiate these two conditions in a clinical setting where most pain assessments are done through simple scale scores.[19] The treatment for OIH may be challenging because of the lack of adequate quality studies published, which is possibly due to the complexity in diagnosis of OIH and challenges in working with patients on chronic opioids. Currently there is no single best pharmacologic treatment for OIH and clinicians are advised to choose an appropriate therapy based on the unique clinical scenario and history of each patient.[19]

One general treatment option is to reduce or discontinue the dose of opioid to see if OIH is improved, although this could induce withdrawal symptoms that may initially increase pain.[19][16][6] Opioid sparing or opioid switching, which refers to the replacement of the current opioid with another pharmacological agent such as morphine or methadone, has been reported to be effective in some studies but this may also increase the sensitivity to pain according to some case reports. Ketamine, an NMDA antagonist, has been shown to prevent the extended use of opioid in post-operative hyperalgesia when it is infused in a small amount perioperatively along with the opioid but there are also studies that show ketamine being ineffective in modulating hyperalgesia. Methadone is also believed to show some efficacy in OIH, presumably due to its weak NMDA antagonist activity. The use of an NSAID, especially some COX-2 inhibitors, or acetaminophen either as monotherapy or combination therapy is also suggested as a possible treatment option.[19][16][6] Mesenchymal stem cell (MSC) therapy has shown efficacy in the treatment of OIH in animal studies.[20] Palmitoylethanolamide (PEA) has been studied for it's anti-inflammatory and analgesic effects and emerging data suggests that it may have a role in delaying the onset of opioid tolerance and reducing the development of OIH when used in conjunction with opioids.[21]


In examining the published studies on opioid-induced hyperalgesia (OIH), Reznikov et al criticize the methodologies employed on both humans and animals as being far-removed from the typical regimen and dosages of pain patients in the real world.[22] They also note that some OIH studies were performed on drug addicts in methadone rehabilitation programs, and that such results are very difficult to generalize and apply to medical patients in chronic pain. In contrast, a study of 224 chronic pain patients receiving 'commonly-used' doses of oral opioids, in more typical clinical scenarios, found that the opioid-treated patients actually experienced no difference in pain sensitivity when compared to patients on non-opioid treatments. The authors conclude that opioid-induced hyperalgesia may not be an issue of any significance for normal, medically-treated chronic pain patients at all.[22]

Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance.[23] The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance).[23]

The suggestion that chronic pain patients who are diagnosed as experiencing opioid-induced hyperalgesia ought to be completely withdrawn from opioid therapy has also been met with criticism. This is not only because of the uncertainties surrounding the diagnosis of OIH in the first place,[22] but because of the viability of rotating the patient between different opioid analgesics over time. Opioid rotation is considered a valid alternative to the reduction or cessation of opioid therapy,[24] and multiple studies demonstrate the rotation of opioids to be a safe and effective protocol.[25][26][27]


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