Opioid-induced hyperalgesia

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Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is an uncommon condition of generalized pain caused by the long-term use of high dosages of opioids [1] such as morphine, [2] oxycodone, [3] and methadone. [4] [5] OIH is not necessarily confined to the original affected site. [6] This means that if the person was originally taking opioids due to lower back pain, when OIH appears, the person may experience pain in the entire body, instead of just in the lower back. Over time, individuals taking opioids can also develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). [6] This means that if the person originally felt pain from twisting or from sitting too long, the person might now additionally experience pain from a light touch or from raindrops falling on the skin.

Contents

OIH differs from drug tolerance, although it can be difficult to tell the two conditions apart. OIH can often be treated by gradually tapering the opioid dose and replacing opioid-based pain care with other pain management medications and techniques or by opioid rotation. [7]

Differentiation from tolerance

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, theorized to occur via two major mechanisms: 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 allodynia. [10] 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. [11] 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.” [12] However, the conclusion of a report published in the Journal of Pain and 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.” [13]

Pharmacology

The pharmacology of opioids involves the substance binding to opioid receptors in the nervous system and other tissues. The three known and defined opioid 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. [14] Two of the most commonly used opioid antagonists at the mu receptor are naltrexone and naloxone. [15] 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). [16]

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). [17]

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 fast 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 more pain relief due to the high expression of CYP2D6, resulting in more codeine being turned into morphine. Poor metabolizers may feel an initial short reduction in pain followed by a quick return to baseline. Patients who are poor metabolizers should be given minimal amounts of opioids such as tramadol and codeine as they do not possess the necessary enzymes to turn it into its active metabolite desmetramadol. 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. [18]

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. [19]

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. [20] 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. [21] [22] [23] 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. [24] 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. [23] [25]

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. [26] it has been shown experimentally that introduction of an NMDA receptor antagonist to mice and rats greatly reduces or even prevents OIH. [27]

B-arrestin 2 transcripts (Arrb2) are implicated in OIH because of their upregulation during analgesic tolerance in the periaqueductal gray, cortex and striatum. [28] NMDA receptor antagonists combined with morphine in OIH conditions have been shown to reduce Arr2b in the entirety of the mouse's brain. [29] 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. [30] Studies that attempted to link LTP and hyperalgesia have found that drugs able to block LTP (ketamine and minocycline) also decrease hyperalgesia. [31] 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. [32] 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. [32]

One general treatment option is to gradually reduce or discontinue the dose of opioid to see if OIH is improved, although this could induce withdrawal symptoms that may initially increase pain. [32] [17] [6]

Opioid switching, also called opioid rotation, is the replacement of the current opioid with another pharmacological agent such as morphine or methadone. It was effective in some studies, but can increase sensitivity to pain, requiring higher doses of the opioid-sparing drug. [33] Opioid rotation is a safe and effective alternative to completely stopping opioid therapy. [34] [35] [36] [37] Methadone is also believed to show some efficacy in OIH, presumably due to its weak NMDA antagonist activity.

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.[ citation needed ]

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. [32] [17] [6]

Research needs

It can be difficult to apply research into OIH to average patients, because some research focused on people taking very high doses or in methadone rehabilitation programs. [38]

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. [39] 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). [39]

a2 agonists, such as clonidine and dexmedetomidine, have been studied as alternatives or adjuncts to opioids for their analgesic properties in the perioperative setting. [40] 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. [40]

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. [41]

See also

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Ketamine</span> Dissociative anesthetic and anti-depressant

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and in pain management. Ketamine is an NMDA receptor antagonist which accounts for most of its psychoactive effects.

<span class="mw-page-title-main">Morphine</span> Pain medication of the opiate family

Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are sold under the brand names MS Contin and Kadian, among others. Generic long-acting formulations are also available.

<span class="mw-page-title-main">Methadone</span> Opioid medication

Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

<span class="mw-page-title-main">Oxycodone</span> Opioid medication

Oxycodone, sold under the brand name Roxicodone and OxyContin among others, is a semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and is a commonly abused drug. It is usually taken by mouth, and is available in immediate-release and controlled-release formulations. Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate-release formulation. In the United Kingdom, it is available by injection. Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, naltrexone, and aspirin.

<span class="mw-page-title-main">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder

Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.

<span class="mw-page-title-main">Hyperalgesia</span> Abnormally increased sensitivity to pain

Hyperalgesia is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.

<span class="mw-page-title-main">Nalbuphine</span> Opioid analgesic

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Codeine</span> Opiate and prodrug of morphine used to treat pain

Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, Papaver somniferum. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications, including a risk of habituation and overdose.

μ-opioid receptor Protein-coding gene in the species Homo sapiens, named for its ligand morphine

The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

<span class="mw-page-title-main">RB-101</span> Chemical compound

RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.

<span class="mw-page-title-main">Oxymorphazone</span> Opioid analgesic

Oxymorphazone is an opioid analgesic drug related to oxymorphone. Oxymorphazone is a potent and long acting μ-opioid agonist which binds irreversibly to the receptor, forming a covalent bond which prevents it from detaching once bound. This gives it an unusual pharmacological profile, and while oxymorphazone is only around half the potency of oxymorphone, with higher doses the analgesic effect becomes extremely long lasting, with a duration of up to 48 hours. However, tolerance to analgesia develops rapidly with repeated doses, as chronically activated opioid receptors are rapidly internalised by β-arrestins, similar to the results of non-covalent binding by repeated doses of agonists with extremely high binding affinity such as lofentanil.

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<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

<span class="mw-page-title-main">(+)-Naloxone</span> Drug

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (−)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

<span class="mw-page-title-main">Rostral ventromedial medulla</span> Group of neurons in medulla of brain

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.

Opioid rotation or opioid switching is the process of changing one opioid to another to improve pain control or reduce unwanted side effects. This technique was introduced in the 1990s to help manage severe chronic pain and improve the opioid response in cancer patients. In order to obtain adequate levels of pain relief, patients requiring chronic opioid therapy may require an increase in the original prescribed dose for a number of reasons, including increased pain or a worsening disease state. Over the course of long-term treatment, an increase in dosage cannot be continued indefinitely as unwanted side effects of treatment often become intolerable once a certain dose is reached, even though the pain may still not be properly managed. One strategy used to address this is to switch the patient between different opioid drugs over time, usually every few months. Opioid rotation requires strict monitoring in patients with ongoing levels of high opioid doses for extended periods of time, since long term opioid use can lead to a patient developing tolerance to the analgesic effects of the drug. Patients may also not respond to the first opioid prescribed to them at all, therefore needing to try another opioid to help manage their pain. A patient's specific response and sensitivity to opioids include many factors that include physiology, genetics and pharmacodynamic parameters, which together determine the amount of pain control and tolerance of a particular opioid.

References

  1. ↑ Higgins, C.; Smith, B. H.; Matthews, K. (June 2019). "Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis". British Journal of Anaesthesia. 122 (6): e114–e126. doi: 10.1016/j.bja.2018.09.019 . ISSN   1471-6771. PMID   30915985.
  2. ↑ Julie L. Cunningham (2013) Opioid induced hyperalgesia: A focus on opioid use in chronic pain. Mental Health Clinician: June 2013, Vol. 2, No. 12, pp. 395–397.
  3. ↑ BNM Group. 2014. Oxycodone (BNM) Data Sheet. 13 March 2014. URL: www.medsafe.govt.nz/profs/Datasheet/o/oxydoneBNMtab.pdf (accessed 22 July 2015).
  4. ↑ Compton P, Charuvastra VC, Ling W (July 2001). "Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent". Drug and Alcohol Dependence. 63 (2): 139–46. doi:10.1016/s0376-8716(00)00200-3. PMID   11376918.
  5. ↑ Compton P, Charuvastra VC, Kintaudi K, Ling W (October 2000). "Pain responses in methadone-maintained opioid abusers". Journal of Pain and Symptom Management. 20 (4): 237–45. doi: 10.1016/s0885-3924(00)00191-3 . PMID   11027904.
  6. 1 2 3 4 Yi P, Pryzbylkowski P (October 2015). "Opioid Induced Hyperalgesia". Pain Medicine. 16 (Suppl 1): S32–6. doi: 10.1111/pme.12914 . PMID   26461074.
  7. ↑ Fishbain, David A.; Pulikal, Aditya (1 November 2019). "Does Opioid Tapering in Chronic Pain Patients Result in Improved Pain or Same Pain vs Increased Pain at Taper Completion? A Structured Evidence-Based Systematic Review". Pain Medicine (Malden, Mass.). 20 (11): 2179–2197. doi:10.1093/pm/pny231. ISSN   1526-4637. PMID   30597076.
  8. ↑ Chu LF, Angst MS, Clark D (2008). "Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations". The Clinical Journal of Pain. 24 (6): 479–96. doi:10.1097/AJP.0b013e31816b2f43. PMID   18574358. S2CID   8489213.
  9. ↑ Leal, Plinio da Cunha (2010). "Opioid-Induced Hyperalgesia (OIH)". Revista Brasileira de Anestesiologia. 60 (6): 639–647. doi: 10.1016/s0034-7094(10)70080-5 . PMID   21146061.
  10. ↑ DuPen A, Shen D, Ersek M (September 2007). "Mechanisms of opioid-induced tolerance and hyperalgesia". Pain Management Nursing. 8 (3): 113–21. doi:10.1016/j.pmn.2007.02.004. PMID   17723928.
  11. ↑ Roeckel, Laurie-Anne; Le Coz, Glenn-Marie; Gavériaux-Ruff, Claire; Simonin, Frédéric (December 2016). "Opioid-induced hyperalgesia: Cellular and molecular mechanisms". Neuroscience. 338: 160–182. doi:10.1016/j.neuroscience.2016.06.029. ISSN   0306-4522. PMID   27346146. S2CID   24008334.
  12. ↑ Wilson, George R.; Reisfield, Gary M. (2003). "Morphine hyperalgesia: A case report". American Journal of Hospice and Palliative Medicine. 20 (6): 459–461. doi:10.1177/104990910302000608. PMID   14649563. S2CID   22690630.
  13. ↑ Vella-Brincat, Jane; Macleod, A. D. (2007). "Adverse Effects of Opioids on the Central Nervous Systems of Palliative Care Patients" (PDF). Journal of Pain and Palliative Care Pharmacotherapy. 21 (1): 15–25. doi:10.1300/J354v21n01_05. PMID   17430825.
  14. ↑ Al-Hasani, Ream (December 2011). "Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior". Anesthesiology. 115 (6): 1363–1381. doi:10.1097/ALN.0b013e318238bba6. PMC   3698859 . PMID   22020140.
  15. ↑ Goodman, Allan (2 November 2007). "Mu Opioid Receptor Antagonists: Recent Developments". ChemMedChem. 2 (11): 1552–1570. doi:10.1002/cmdc.200700143. PMID   17918759. S2CID   22243459.
  16. ↑ Katzung BG, Trevor AJ (2014-12-23). Basic and clinical pharmacology. Katzung, Bertram G., Trevor, Anthony J. (Thirteenth ed.). New York. ISBN   978-0071825054. OCLC   875520239.{{cite book}}: CS1 maint: location missing publisher (link)
  17. 1 2 3 Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L (2011). "A comprehensive review of opioid-induced hyperalgesia". Pain Physician. 14 (2): 145–61. doi: 10.36076/ppj.2011/14/145 . PMID   21412369.
  18. ↑ Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE (July 2014). "PharmGKB summary: tramadol pathway". Pharmacogenetics and Genomics. 24 (7): 374–80. doi:10.1097/FPC.0000000000000057. PMC   4100774 . PMID   24849324.
  19. ↑ Drdla R, Gassner M, Gingl E, Sandkühler J (July 2009). "Induction of synaptic long-term potentiation after opioid withdrawal". Science. 325 (5937): 207–10. Bibcode:2009Sci...325..207D. doi:10.1126/science.1171759. PMID   19590003. S2CID   9591736.
  20. ↑ Roeckel, Laurie-Anne; Le Coz, Glenn-Marie; Gavériaux-Ruff, Claire; Simonin, Frédéric (2016). "Opioid-induced hyperalgesia: Cellular and molecular mechanisms". Neuroscience. 338: 160–182. doi:10.1016/j.neuroscience.2016.06.029. ISSN   0306-4522. PMID   27346146. S2CID   24008334.
  21. ↑ Law, Ping-Yee; Reggio, Patricia H.; Loh, Horace H. (2013). "Opioid receptors: toward separation of analgesic from undesirable effects". Trends in Biochemical Sciences. 38 (6): 275–282. doi:10.1016/j.tibs.2013.03.003. ISSN   0968-0004. PMC   3665630 . PMID   23598157.
  22. ↑ Pasternak, Gavril W.; Pan, Ying-Xian; Sibley, David R. (2013). "Mu Opioids and Their Receptors: Evolution of a Concept". Pharmacological Reviews. 65 (4): 1257–1317. doi:10.1124/pr.112.007138. ISSN   0031-6997. PMC   3799236 . PMID   24076545.
  23. 1 2 Convertino, Marino; Samoshkin, Alexander; Gauthier, Josee; Gold, Michael S.; Maixner, William; Dokholyan, Nikolay V.; Diatchenko, Luda (2015). "μ-Opioid receptor 6-transmembrane isoform: A potential therapeutic target for new effective opioids". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 62: 61–67. doi:10.1016/j.pnpbp.2014.11.009. ISSN   0278-5846. PMC   4646084 . PMID   25485963.
  24. ↑ Gris, Pavel; Gauthier, Josee; Cheng, Philip; Gibson, Dustin G; Gris, Denis; Laur, Oskar; Pierson, John; Wentworth, Sean; Nackley, Andrea G; Maixner, William; Diatchenko, Luda (2010). "A Novel Alternatively Spliced Isoform of the Mu-Opioid Receptor: Functional Antagonism". Molecular Pain. 6: 1744-8069–6-33. doi: 10.1186/1744-8069-6-33 . ISSN   1744-8069. PMC   2894766 . PMID   20525224.
  25. ↑ Taylor, Bradley; Oladosu, Folabomi A.; Conrad, Matthew S.; O’Buckley, Sandra C.; Rashid, Naim U.; Slade, Gary D.; Nackley, Andrea G. (2015). "Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia". PLOS ONE. 10 (8): e0135711. Bibcode:2015PLoSO..1035711O. doi: 10.1371/journal.pone.0135711 . ISSN   1932-6203. PMC   4535978 . PMID   26270813.
  26. ↑ Antal, M.; Fukazawa, Y.; Eordogh, M.; Muszil, D.; Molnar, E.; Itakura, M.; Takahashi, M.; Shigemoto, R. (2008). "Numbers, Densities, and Colocalization of AMPA- and NMDA-Type Glutamate Receptors at Individual Synapses in the Superficial Spinal Dorsal Horn of Rats". Journal of Neuroscience. 28 (39): 9692–9701. doi: 10.1523/JNEUROSCI.1551-08.2008 . ISSN   0270-6474. PMC   3844880 . PMID   18815255.
  27. ↑ Li, Xiangqi; Angst, Martin S; Clark, J.David (2001). "A murine model of opioid-induced hyperalgesia". Molecular Brain Research. 86 (1–2): 56–62. doi:10.1016/S0169-328X(00)00260-6. ISSN   0169-328X. PMID   11165371.
  28. ↑ Bohn, Laura M.; Gainetdinov, Raul R.; Lin, Fang-Tsyr; Lefkowitz, Robert J.; Caron, Marc G. (2000). "μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence". Nature. 408 (6813): 720–723. Bibcode:2000Natur.408..720B. doi:10.1038/35047086. ISSN   0028-0836. PMID   11130073. S2CID   4356525.
  29. ↑ Sommer, Claudia; Ohnesorge, Henning; Feng, Zhiying; Zitta, Karina; Steinfath, Markus; Albrecht, Martin; Bein, Berthold (2013). "Influence of Clonidine and Ketamine on m-RNA Expression in a Model of Opioid-Induced Hyperalgesia in Mice". PLOS ONE. 8 (11): e79567. Bibcode:2013PLoSO...879567O. doi: 10.1371/journal.pone.0079567 . ISSN   1932-6203. PMC   3815130 . PMID   24223972.
  30. ↑ Liu, X.-G.; Sandkühler, J. (1997). "Characterization of Long-Term Potentiation of C-Fiber–Evoked Potentials in Spinal Dorsal Horn of Adult Rat: Essential Role of NK1 and NK2 Receptors". Journal of Neurophysiology. 78 (4): 1973–1982. doi:10.1152/jn.1997.78.4.1973. ISSN   0022-3077. PMID   9325365.
  31. ↑ Klein, T.; Magerl, W.; Nickel, U.; Hopf, H. C.; Sandkühler, J.; Treede, R. D. (2007). "Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system". Neuropharmacology. 52 (2): 655–61. doi:10.1016/j.neuropharm.2006.09.008. PMID   17084865. S2CID   143840.
  32. 1 2 3 4 Ramasubbu C, Gupta A (2011). "Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence". Journal of Pain & Palliative Care Pharmacotherapy. 25 (3): 219–30. doi:10.3109/15360288.2011.589490. PMID   21834699. S2CID   33155060.
  33. ↑ Mercadante, Sebastiano; Bruera, Eduardo (2006-06-01). "Opioid switching: A systematic and critical review". Cancer Treatment Reviews. 32 (4): 304–315. doi:10.1016/j.ctrv.2006.03.001. ISSN   0305-7372. PMID   16624490.
  34. ↑ Mitra S (2018). "Opioid-induced hyperalgesia: pathophysiology and clinical implications". Journal of Opioid Management. 4 (3): 123–30. doi:10.5055/jom.2008.0017. PMID   18717507.
  35. ↑ Fine PG (2004). "Opioid insights:opioid-induced hyperalgesia and opioid rotation". Journal of Pain & Palliative Care Pharmacotherapy. 18 (3): 75–9. doi:10.1080/J354v18n03_08. PMID   15364634. S2CID   45555785.
  36. ↑ Mercadante S, Arcuri E (2005). "Hyperalgesia and opioid switching". The American Journal of Hospice & Palliative Care. 22 (4): 291–4. doi:10.1177/104990910502200411. PMID   16082916. S2CID   39647898.
  37. ↑ González-Barboteo J, Alentorn XG, Manuel FA, Candel VA, Eito MA, Sánchez-Magro I, Álvarez MN, Martín FJ, Porta-Sales J (2014). "Effectiveness of opioid rotation in the control of cancer pain: the ROTODOL study". Journal of Opioid Management. 10 (6): 395–403. doi:10.5055/jom.2014.0236. PMID   25531957. S2CID   31136231.
  38. ↑ Reznikov I, Pud D, Eisenberg E (September 2005). "Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain". British Journal of Clinical Pharmacology. 60 (3): 311–8. doi:10.1111/j.1365-2125.2005.02418.x. PMC   1884770 . PMID   16120071.
  39. 1 2 Chen L, Sein M, Vo T, Amhmed S, Zhang Y, Hilaire KS, Houghton M, Mao J (2014). "Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia". Journal of Opioid Management. 10 (6): 383–93. doi:10.5055/jom.2014.0235. PMID   25531956.
  40. 1 2 Blaudszun, Grégoire; Lysakowski, Christopher; Elia, Nadia; Tramèr, Martin R. (2012-06-01). "Effect of Perioperative Systemic α2 Agonists on Postoperative Morphine Consumption and Pain IntensitySystematic Review and Meta-analysis of Randomized Controlled Trials". Anesthesiology. 116 (6): 1312–1322. doi: 10.1097/ALN.0b013e31825681cb . ISSN   0003-3022. PMID   22546966.
  41. ↑ Varrassi G, Fusco M, Skaper SD, Battelli D, Zis P, Coaccioli S, Pace MC, Paladini A (June 2018). "A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review". Pain and Therapy. 7 (1): 59–75. doi:10.1007/s40122-018-0094-9. PMC   5993687 . PMID   29594972.
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