Opioid-induced hyperalgesia

Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is a phenomenon associated with the long-term use of opioids such as morphine, oxycodone, and methadone. OIH is characterized as generalized pain that is not necessarily confined to the affected site. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids. Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is a phenomenon associated with the long-term use of opioids such as morphine, oxycodone, and methadone. OIH is characterized as generalized pain that is not necessarily confined to the affected site. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids. 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. 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). In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodynia. In addition, what appears to be opioid tolerance can be caused by opioid-induced hyperalgesia lowering the baseline pain level, thus masking the drug's analgesic effects. 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. The phenomenon is common among palliative care patients following a too rapid escalation of opioid dosage. 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. Two of the most commonly used opioid antagonists at the mu receptor are naltrexone and naloxone. 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). 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). 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. The enzyme CYP2D6 is used to metabolize several opioids including codeine, methadone, hydrocodone, and tramadol. 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 the dose of 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. 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 central nervous system, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn. One possible strategy for treating hyperalgesia involves blocking activation of these receptors with NMDA receptor 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 NMDA receptor 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 NMDA receptor 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. 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. 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. 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. 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, requiring higher doses of the opioid sparing drug. 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. a2 agonists, such as clonidine and dexmedetomidine, have been studied as alternatives or adjuncts to opioids for their analgesic properties in the perioperative setting. They have been shown to decrease the need for opioids after surgery, which may reduce the risk of hyperalgesic effects associated with prolonged opioid use. However, there is currently insufficient data to support the clinical effectiveness of a2 agonists in reducing postoperative OIH. Mesenchymal stem cell (MSC) therapy has shown efficacy in the prevention and treatment of OIH in animal studies. Palmitoylethanolamide (PEA) has been studied for its 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.