Opioid-induced hyperalgesia

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,[4] oxycodone,[5] and methadone.[6][7] OIH is characterized as generalized pain that is not necessarily confined to the affected site.[8] Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia).[8] Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.[9]

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.[10] 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).[11] In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodynia.[12] 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.[13] 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.

This “uncommon but important phenomenon [can be] seen with high-dose opioid therapy.” [14] However, the conclusion of a report published in the Journal of Pain & Palliative Care Pharmacotherapy suggests that “[h]yperalgesia shares a common mechanism with tolerance and it may be that hyperalgesia is a manifestation of tolerance itself.” [15]

Pharmacology
See also: Opioid § Pharmacology

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.[16] Two of the most commonly used opioid antagonists at the mu receptor are naltrexone and naloxone.[17] 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).[18]

Pharmacogenomics

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).[19]

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, an ultra-rapid metabolizer will feel very little pain relief while a poor metabolizer may feel a large reduction in pain. Conversely patients who are poor 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.[20]

Mechanism of action

The sensitization of pronociceptive pathways in response to opioid treatment appears to involve several pathways. Research thus far has primarily implicated the μ-opioid receptors (MOR) 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.[21]

μ-opioid receptors

In clinical trials, the MOR is the main target of opioid ligand binding. While binding of the opioid to the MOR typically causes analgesia, there can be instances where hyperalgesia occurs. [22] It has been speculated that the opposite analgesic and hyperanalgesic effects are due to different isoforms of the receptor. The MOR is a G protein-coupled receptor with seven transmembrane domains. Variants of the receptor have been discovered and are due to alternative splicing mechanisms.[23][24][25] A particular receptor variant, 6TM MOR, has been heavily studied because of its role in nociception. The 6TM MOR is missing residues in the N-terminal region which has implications for the extracellular tail and first transmembrane domain. This causes an excitatory effect compared to the inhibition in the normal seven transmembrane domain receptor because of differences in G-protein activation.[26] Studies on mice have shown silencing of the 6TM MOR variant decreased morphine-induced hyperalgesia which suggested G-protein coupling in the 6TM isoform could be a factor in the development of OIH.[25][27]

NMDA Receptors

OIH shares commonalities with chronic pain in their neural mechanisms and specifically their usage of the glutaminergic system and NMDA glutamate receptors. NMDA receptors can be found presynaptically on central terminals of primary afferent neurons and postsynaptically on spinal dorsal horn neurons. [28] it has been shown experimentally that introduction of an NMDA receptor antagonist to mice and rats greatly reduces or even prevents OIH.[29]

B-arrestin 2 transcripts (Arrb2) are implicated in OIH because of their upregulation during analgesic tolerance in the periaqueductal gray, cortex and striatum.[30] NMDA receptor antagonists combined with morphine in OIH conditions have been shown to reduce Arr2b in the entirety of the mouse's brain. [31] These findings implicate Arr2b activity as a factor in OIH.

Long-Term Potentiation

Long-Term Potentiation (LTP) is the increase in sensitivity of homosynapses that augment the synapse's strength and signal transduction. In the context of OIH, LTP has been shown to contribute to hyperalgesia by hypersensitizing areas of nociceptive processing, particularly at synapses between C fibers and the spinal cord dorsal horn. [32]Studies that attempted to link LTP and hyperalgesia have found that drugs able to block LTP (ketamine and minocycline) also decrease hyperalgesia.[33] In addition, LTP and OIH both utilize NMDA receptors and their activity can be reduced by NMDA receptor antagonists (i.e. ketamine).

Management

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.[34] 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.[34]

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.[34][19][8] 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.[35] 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.[34][19][8] a2 agonists, such as clonidine and dexmedetomidine, have been studied as alternatives or adjuncts to opioids for their analgesic properties in the perioperative setting.[36] 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.[36] Mesenchymal stem cell (MSC) therapy has shown efficacy in the prevention and treatment of OIH in animal studies.[37] 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.[38]

Criticism

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.[39] 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.[39]

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.[40] 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).[40]

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,[39] 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,[41] and multiple studies demonstrate the rotation of opioids to be a safe and effective protocol.[42][43][44]

See also

References
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