Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity , also called paradox hyperalgesia is a phenomenon associated with long-term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop increased sensitivity to harmful stimuli, even evolving painful responses to previous non-hazardous stimuli (allodynia). Some animal studies also show this effect occurs after only one high dose of opioids.
Tolerance, other conditions that may arise from prolonged exposure to opioids, can often be misinterpreted as opioid-induced hyperalgesia and vice versa, since clinical presentation may appear similar. Although opioid-induced tolerance and hyperalgesia both result in the same need for dose escalation to receive the same level of effect to treat pain, they are still caused by two different mechanisms. The same clean effect makes two phenomena difficult to distinguish in a clinical setting. Under the treatment of chronic opioids, certain individual requirements 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 through two main theories: decreased receptor activation (desensitization of antinociceptive mechanisms), and opioid receptor down-regulation (internalization of membrane receptors). In opioid-induced hyperalgesia, pronociceptive mechanism sensitization occurs, resulting in a decrease in pain threshold, or allodyna. Identifying the development of hyperalgesia is of clinical importance because patients receiving opioids for pain relief can paradoxically experience more pain as a result of treatment. While increasing the dose of opioids can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hypalgesia can worsen the patient's condition by increasing the sensitivity to pain while increasing physical dependence.
This phenomenon is common among palliative care patients after escalation of opioid doses too quickly.
Video Opioid-induced hyperalgesia
Pharmacology
See also: Opioid # Pharmacology
Opioid pharmacology involves a substance that binds opioid receptors in the nervous system and other tissues. Three known and undefined receptors are mu, kappa and delta, with many other receptors being reported as well. These receptors are important for binding opioids and eliciting an analgesic response, thereby reducing the pain sensation. Pharmacology for opioid-induced opioid hyperalgesia is more complicated, and it is believed to involve activation of NMDA receptors and increased excitatory peptide neurotransmitters (such as cholecystokinin.)
Maps Opioid-induced hyperalgesia
Pharmacogenomics
There is growing evidence supporting genetics to be a key factor in OIH development through its influence on pain sensitivity and analgesic control. Current evidence suggests that genetic influences originate from the gene polymorphism that encodes the enzyme, Catechol-O-Methyltransferase (COMT). Its enzymatic activity varies depending on three possible genotypes, seen as a single amino acid change from valine to methionine, resulting in significant variability in its activity. The degradation of neurotransmitters, dopamine and noradrenaline, is about 4 times larger when the amino acids presented are valine, not methionine. This results in modulation of dopaminergic and noradrenergic responses at the synaptic level of neurons, which has been associated with having an effect on memory function, anxiety, and pain sensitivity compared to individuals present as homozygous for valine alleles of this particular gene (COMTval158).
Action mechanism
The exact mechanisms underlying opioid-induced hyperalgesia are poorly understood. The sensitization of the pronociceptive pathway in response to opioid therapy seems to involve multiple pathways. Research thus far primarily involves abnormal activation of NMDA receptors in CNS, and long-term potential synapses between nociceptive C fibers and neurons in the dorsal dorsal spinalis. One possible strategy for treating hyperalgesia involves blocking the activation of these receptors with NMDAR antagonists such as ketamine, dextromethorphan, or methadone (which have NMDAR antagonist properties in addition to being opioid analgesics). Human studies that examine the benefits of combining opioid treatment with NMDAR antagonism have produced mixed results, and some conclusions can be drawn until greater research is undertaken. Targeting NMDA receptors in potential pathological areas (such as dorsal bone marrow horns) is a challenge given their widespread presence throughout the spinal cord and brain, and profound psychotomimetic side effects associated with NMDAR antagonists known to limit their clinical potential as adjuvants to pain treatment. Gliosis due to the agonist effect of opioid TLR4 has also been implicated in hyperalgesia and tolerance.
Management
Treatment of opioid and Opioid-Induced Hyperalgesia (OIH) tolerance is different but it may be difficult to distinguish between these two conditions in a clinical setting where most pain assessments are performed through simple scale scores. Treatment for OIH may be challenging because insufficient amount of quality research may be due to the complexity in OI diagnosis and challenges in working with patients on chronic opioids. Currently there is no best treatment method for OIH and doctors are advised to choose the right therapy based on unique clinical scenarios and history of each patient.
One common treatment option is to reduce or stop the opioid dose to see if OIH improves. Expensive opioids or opioid switching, which replaces current opioids with other pharmacological agents such as morphine or methadone, have been reported to be effective in some studies but this can also increase pain sensitivity according to some case reports. Ketamine, an NMDA antagonist, has been shown to prevent the use of opioids in postoperative hyperalgesia when infused in small quantities perioperatively along with opioids but there are also studies that show ketamine to be ineffective in the modulation of hyperalgesia. The addition of NSAIDs, especially some COX-2 inhibitors, or acetaminophen is also suggested as a possible treatment option.
Criticism
The following criticisms seem to come from patients who want narcotic pain medication. There is no solid clinical evidence to support the use of chronic opioid therapy that is safe and effective for non-malignant pain. Patients and providers should avoid this treatment. OIH is just one of many reasons to stop patients from chemical dependence.
In examining published studies on opioid-induced hyperalgesia (OIH), Reznikov et al criticized the methodologies used in both humans and animals as far-removed from the typical regimen and dosage of pain patients in real world. They also noted that some OIH studies were conducted on drug addicts in a methadone rehab program, and that these results are very difficult to generalize and apply to medical patients in chronic pain. In contrast, a study of 224 patients with chronic pain who received orally used oral opioid doses, in a more typical clinical scenario, found that opioid-treated patients did not experience a difference in pain sensitivity when compared with patients undergoing non- opioid.. The authors concluded that opioid-induced hyperalgesia may not be a matter of significance for chronic pain patients treated medically altogether.
Opioid-induced hyperalgesia is also criticized for being overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the more common phenomenon of opioid tolerance. Misdiagnosis of general opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) may be a problem because the clinical actions suggested by each condition may conflict with each other. Patients misdiagnosed with OIH may have their dose of opioid erroneously decreased (in an attempt to counteract OIH) at a time when it is completely appropriate for their dose to be upgraded or rotated (as counter to opioid tolerance).
The suggestion that patients with chronic pain diagnosed with opioid-induced hyperalgesia should be entirely withdrawn from opioid therapy has also been criticized. This is not only because of the uncertainty surrounding the diagnosis of OIH in the first place, but because the viability rotates the patient between different opioid analgesics over time. Opioid rotation is considered a valid alternative to the reduction or discontinuation of opioid therapy, and several studies have shown opioid rotation to be a safe and effective protocol.
References
Source of the article : Wikipedia
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