Look is their chest moving? If they are breathing even a little, but are not responsive, you can help with rescue breathing. Stick with them for a few hours and keep an eye on them, because there is always the chance that a real overdose could develop. Signs of an overdose include slow or shallow breathing, pale and clammy skin, snoring or gurgling while asleep and unresponsiveness to yelling or physical stimulation. If you suspect that someone may have overdosed call Additional steps you may take include rescue breathing and giving narcan, if available.
Call right away: Give them the address, tell them your friend is not breathing, stay calm and follow their instructions. Narcan may save their life but must be given quickly. They may need more than one dose. UConn Health. Search University of Connecticut. A to Z Index. What are opioids? What is an overdose? What are some common opioids I may have heard of? What are some addiction warning signs to watch out for? Taking opioid medications for the feeling of pleasure or euphoria or for emotional escape People suggesting that you cut back or quit using the medications Taking the medications other than orally such as crushing and snorting, or injecting Having cravings when not taking the drugs Seeking early refills of prescriptions, prescriptions from other doctors, or drugs from other sources What are some tips for patients with pain medication?
Do not increase your dosage without consulting your doctor Be aware of potential interactions with other substances, such as alcohol, antihistamines, anti-anxiety drugs such as benzodiazepines, and sleep aids Do not sell or give your medications to others, or accept medications from other sources than a pharmacy Tell your doctor about any other drugs you take, including over-the-counter medicines and street drugs Tell your doctor if you have a history of substance abuse, an addictive personality, or are experiencing any of the warning signs of addiction What are some of the signs of an opioid overdose?
Finally, claims made on your Facebook page, www. New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from the FDA, as described in sections d and a of the Act [21 U. FDA approves a new drug on the basis of scientific data and information demonstrating that the drug is safe and effective. A drug is misbranded under section f 1 of the Act [21 U.
Prescription drugs, as defined in section b 1 A of the Act [21 U. Therefore, it is impossible to write adequate directions for a layperson to use your products safely for their intended purposes. The introduction or delivery for introduction into interstate commerce of these misbranded drugs violates section a of the Act [21 U. The violations cited in this letter are not intended to be an all-inclusive list of violations that exist in connection with your products.
In absence of modification on the downstream signaling pathway, G protein uncoupling is a good marker for desensitization but can't be applied for G protein-independent pathways i.
The comparison between desensitization studies suffers also from the various experimental conditions used. Cellular model, agonist, agonist concentration, time of exposure, level of OR expression or signaling pathway studied are among the different parameters that could influence OR desensitization as previously reviewed Connor et al.
As indicated above, desensitization is defined as a progressive reduction of signal transduction that occurs more or less rapidly after OR activation depending on the agonist and the signaling pathway. The rapid desensitization is mainly observed on the regulation of ion channel conductance from sec to several minutes while a sustained desensitization is rather observed on regulation of enzymes ACase, MAP kinases after minutes to several tens of minutes.
However, in this latter case, other counter-regulatory mechanisms internalization, traffic of OR could participate to desensitization making its description complex. Molecular mechanisms turned out to be complicated for several reasons:. In homologous desensitization, only agonist-activated receptors are desensitized while in heterologous desensitization, both agonist-activated and non-activated receptors sharing the same signaling pathways are inactivated.
Those types of desensitization are related to different mechanisms especially in terms of receptor phosphorylation and kinases Chu et al. Cross-desensitization between OR and other GPCRs is not systematically investigated and when it is, the level of desensitization between GPCRs using the same signaling pathway can be different Namir et al.
Recently, Xu et al. Recently, desensitization of MOR expressed in the neurons from locus coeruleus was demonstrated to result from a decrease of both number of active receptors and the affinity of residual receptors for the agonist Williams, This part will discuss recent data from literature regarding desensitization of the different OR: the impact of the agonist used through the notion of biased agonism, the role of phosphorylation and consequently the kinases involved, the implication of arrestins and OR internalization and their fate after endocytosis.
Regarding MOR, a recent review has been published concerning the molecular mechanisms involved in its regulation Williams et al. Few studies have been designed to evaluate the impact of biased agonism on OR desensitization. They would require determination of the relationship between agonist concentration and the response from a large panel of ligands. More generally, the comparison of the ability of two ligands to promote OR desensitization is realized using the same concentration regardless their intrinsic efficacy.
However, such difference was not reported by others Liu and Prather, ; Borgland et al. All those discrepancies could be due to the different level of OR expression, the cellular models and the existence of spare receptors as previously mentioned Connor et al.
Evidence for a different DOR regulation by methadone and morphine was also reported; a pretreatment with methadone but not with morphine produced a cross-desensitization with [D-Ala 2 , D-Leu 5 ]-enkephalin DADLE and morphine Liu et al.
Similar data were reported by Bot et al. Very few studies examined the regulation of KOR by different agonists. With respect to desensitization, all those data support the idea that agonists are able to promote a different regulation of OR as demonstrated for other GPCR such as the histamine H2 receptors Alonso et al.
Such differential desensitization demonstrated for each OR by different agonists is probably related to the set of different regulatory molecular mechanisms see above. Numerous studies have been carried out to demonstrate the role of OR phosphorylation in desensitization by using chemical inhibitors of kinases, in vitro or in vivo knock-out KO of kinases using siRNA or transgenic mice, over-expression of dominant negative mutants of kinases, amino acid substitution or truncation on OR.
While in some studies the phosphorylation state of OR is clearly determined, in most of them and especially those using kinase inhibitors this major information is lacking. All those data are summarized in Figures 1A—C. Figure 1. A Phosphorylation sites of MOR. The S equivalent to S in human is phosphorylated in the absence of agonist El Kouhen et al. PKC was demonstrated to phosphorylate S Chen et al. PKC Illing et al. This agonist-mediated phosphorylation does not implicate PKC Illing et al.
Y Clayton et al. B Phosphorylation sites of DOR. S and S Guo et al. Deltorphin II and morphine are also able to increase phosphorylation at S Navratilova et al. T is phosphorylated by CDK5 in the absence and in the presence of chronic morphine exposure Xie et al.
C Phosphorylation sites of KOR. MOR phosphorylation. Those results were recently confirmed using specific antibodies directed against the phospho-S, phospho-T and phospho-S Doll et al. As demonstrated for the DOR see below , agonist-induced MOR phosphorylation is carried out hierarchically with first of all the S, considered as the major phosphorylation site, followed by T El Kouhen et al.
Interestingly, low concentrations of this opioid agonist rather promote phosphorylation at S and T while a strong phosphorylation of T and S is observed at higher concentrations Just et al. Phosphorylation studies using liquid chromatography-mass spectrometry techniques have led to the characterization of two regions at the C terminal tail of the MOR Lau et al.
Different kinases are involved in MOR phosphorylation. In summary, those studies revealed that S is the main phosphorylation site of MOR but agonists promote a differential and a multi-phosphorylation of this OR as recently reviewed Mann et al. DOR phosphorylation. Pei and colleagues were the first to demonstrate that OR could be phosphorylated upon agonist stimulation Pei et al.
KOR phosphorylation. Concerning KOR phosphorylation, the data from literature are very scarce. Upon global evaluation of the hKOR phosphorylation, Li et al. It is noteworthy that human and rodent KOR differ substantially in the amino acid composition in the C-terminal region; such difference could explain the absence of rKOR phosphorylation when activated by U50, Li et al. In summary, the phosphorylation sites for each OR were mapped and showed that activation of a given receptor by different agonists results in a specific pattern involving different kinases Figures 1A—C.
Any process interfering with the interaction between G proteins and OR can lead to reduction of signal transduction intensity. Conversely, after 5 days of chronic morphine exposure, it is possible to observe a complete uncoupling between MOR and its cognate G proteins Bohn et al. In most of these studies, the role of OR phosphorylation in desensitization is indirectly demonstrated by using KO mice or kinases chemical inhibitors; in such situations, we cannot rule out the phosphorylation of other signaling proteins involved in regulatory mechanisms of OR.
Mutation of putative phosphorylation sites or truncation of the C terminal tail of OR have been extensively used to delineate the role of phosphorylation in desensitization. All those data are summarized in the Table 1. Recently, in locus coeruleus neurons and using chemicals activators phorbol,dibutyrate and phorbolmyristateacetate or a muscarinic agonist known to activate PKC, acute or sustained desensitization of MOR induced either by morphine or [Met 5 ]-enkephalin were demonstrated to differentially required PKC activity but such effects were not inhibited by the potent PKC inhibitor staurosporine Arttamangkul et al.
The role of phosphorylation in MOR desensitization has been challenged: using staurosporine as a broad spectrum kinase inhibitor and a GRK2-mutant mice, Arttamangkul et al. Using chemical inhibitor and KO mice, c-Jun amino-terminal kinase 2 JNK2 was demonstrated to play a major role in morphine- but not fentanyl-induced G protein uncoupling Melief et al. Some studies were also conducted to identify the amino acids of MOR involved in desensitization.
The TA substitution abolished MOR desensitization compared to wild type but the phosphorylation state of the receptor was not evaluated Celver et al. MOR desensitization and phosphorylation at S produced by morphine can be modulated by other proteins such as the FK binding protein 12 which would compete with kinase at MOR Yan et al.
While all those data indicate that MOR phosphorylation would play a crucial role in desensitization, Qiu and collaborators showed that a truncated mutant of MOR from S is able to undergo a similar desensitization to the wild type demonstrating that receptor phosphorylation is not an absolute prerequisite for desensitization Qiu et al. However, phosphorylation would rather regulate MOR traffic which could indirectly impact receptor desensitization see Relationship between OR Internalization and Desensitization.
Tyrosine kinases were also suggested to participate in DOR desensitization. Hong and collaborators found that DPDPE promotes a tyrosine phosphorylation of DOR which would recruit and activate Src that in turn could phosphorylate and activate GRK2; this latter would then phosphorylates S and triggers desensitization Hong et al.
While deltorphin II promotes a rapid receptor phosphorylation at this amino acid and desensitization on the cAMP pathway, this latter is totally abolished in the SA mutant Navratilova et al. However, those authors did not evaluate the phosphorylation at this residue. This indicates that other mechanisms than phosphorylation could contribute to receptor desensitization. In the Xenopus oocyte expression system, examination of rKOR regulation on the activation of potassium channels revealed that over-expression of GRK3 or 5 alone did not promote a significant desensitization which requires both GRK and arrestin 3 Appleyard et al.
Truncation of the C terminal tail of the receptor or the substitution SA severely impaired U69,induced desensitization. These data were further confirmed when wild type and mutant rKOR were expressed in the pituitary adenoma cell line atT cells Mclaughlin et al.
As indicated above, S is the major phosphorylation site for hKOR and the SN substitution totally abolished U50,induced receptor uncoupling from G proteins Li et al. While most of those studies with either indirect or direct proofs indicate the role of OR phosphorylation in desensitization, some of them clearly ruled out such paradigm. This probably indicates that phosphorylation is not a prerequisite for desensitization but would accelerate such process.
As expected, those proteins were also demonstrated to regulate OR functions. For instance, morphine was demonstrated to behave as a partial agonist for DOR and MOR in G protein coupling experiments while almost no interaction with arrestins was detected. This indicates that all opioid ligands do not have the same potency to promote OR desensitization.
Relationship between arrestins and OR desensitization. Genetic ablation of arrestin 3 significantly reduces MOR uncoupling from G proteins upon chronic morphine treatment Bohn et al. Using dorsal root ganglion neurons from arrestin 3 KO mice, the role of this protein in mediating inhibitory regulation of MOR by JNK on voltage-dependent calcium channels was evidenced Mittal et al.
However, in dorsal root ganglion neurons obtained from arrestin 3 KO mice, acute MOR desensitization elicited by DAMGO or morphine on the inhibition of voltage-gated calcium channels was not significantly different from wild type mice indicating that arrestin 3 has no major role in those conditions Walwyn et al. In the Xenopus oocyte, over-expression of arrestin alone is not sufficient to increase DOR Kovoor et al. However, such potentiation could be obtained either when arrestin and a GRK are co-expressed or when the constitutive active arrestin mutant RE is present.
This suggests that OR phosphorylation is a pre-requisite for arrestin action. This conclusion is in good agreement with the data obtained by Johnson et al. In contrast, no such translocation could be detected in morphine-treated cells which produce a PKC-dependent MOR desensitization.
All those data indicate that different mechanisms are responsible for OR desensitization: some are arrestin-dependent and requires GRK while others are arrestin-independent. The number of active OR at the cell surface is regulated by two processes: endocytosis and export of neosynthesized receptors. Intuitively, when OR internalization is stimulated by agonist exposure, one could expect a reduction in signal transduction. However, the relationship between the number of OR and the cellular response is not linear.
Internalization of OR has been demonstrated in different models with different technical approaches but some discrepancies have been reported. U50, and dynorphin A , but neither etorphine nor levorphanol, promote a time-, and concentration-dependent internalization of hKOR Li et al. In few publications, MOR was shown to internalize upon morphine exposure. In enteric neurons, morphine promotes a weak internalization of MOR compared to DAMGO as indicated above but chronic morphine exposure results in a significant increase in endocytosis Patierno et al.
The role of OR phosphorylation in endocytosis was mainly investigated using OR mutants defective in phosphorylation. The truncated MOR from S, which is not phosphorylated by DAMGO treatment, was shown to internalize but with a slower rate than the wild type receptor during the first 30 min Qiu et al.
Herkinorin, a MOR agonist, is unable to promote both phosphorylation and internalization indicating that the two processes could be linked Groer et al. More than a selective phosphorylation on a specific residue of the carboxy-terminal tail of the receptor, the level of MOR internalization would be correlated to the multi-phosphorylation of T, S, T, and T Just et al. However, this DOR mutant cannot internalize anymore when arrestin 3 expression is knocked-down suggesting that the non-phosphorylated DOR can internalize but in an arrestin 3-dependent manner.
When the major site of phosphorylation of DOR is mutated SA , it is possible to observe a deltorphin I-induced endocytosis Navratilova et al. This is in contrast with the study of Bradbury et al. Concerning the rKOR, the phosphorylation-defective mutant SE is unable to internalize upon U50, exposure demonstrating the role of receptor phosphorylation in endocytosis Mclaughlin et al.
Other proteins involved in internalization could also be phosphorylated as demonstrated for the MOR. Activation of phospholipase D2 would enhance MOR endocytosis by the activation of p38 kinase which in turn phosphorylates the Rab5 effector early endosome antigen 1 required for this process Yang et al. The involvement of arrestins in OR internalization was demonstrated by direct selective knock-down of arrestin expression or indirect approaches visualization of arrestin translocation to plasma membrane Table 2.
DAMGO-induced MOR internalization in striatal neurons is impaired by over-expression of a dominant negative mutant of arrestin 2 corresponding to the last amino acids arrestin 2 — Haberstock-Debic et al. Etorphine also induces an arrestin-dependent MOR internalization as shown by the reduction of receptor endocytosis when the dominant negative mutant V53D of arrestin is over-expressed Zhang et al.
Whereas over-expression of arrestin 2 alone has not significant impact, over-expression of GRK2 greatly enhances receptor sequestration; such GRK2-mediated MOR internalization is potentiated when both kinase and arrestin 2 are both co- and over-expressed Zhang et al. The lack of MOR internalization upon activation with herkinorin would be due to the absence of interaction between receptor and arrestin 3 Groer et al.
The constitutive MOR internalization is also arrestin 3-dependent Walwyn et al. Whereas those reports indicate the crucial role of arrestins in MOR endocytosis, this was recently challenged by Quillinan et al.
In a recent work, the group of von Zastrow showed that after being recruited by the phosphorylated MOR, arrestin 3 acts as a scaffold, promoting ubiquitination of two lysyl residues in the first intracellular loop by the ubiquitin ligase Smurf2 Henry et al.
Epsin 1, through its ubiquitin-interacting motifs, recognizes the ubiquitinated MOR contained in the clathrin-coated pits and triggers scission of the vesicle from the cell surface.
Those data revealed new inter-relations between MOR phosphorylation and ubiquitination with internalization. DPDPE also enables arrestin-mediated endocytosis of DOR as shown by the partial reduction of internalization when arrestins 2 or 3 are selectively inhibited Zhang et al. DOR endocytosis is severely impaired in MEFs obtained from single KO mice for arrestin 2 indicating a preferential interaction between those two proteins Qiu et al.
It is noteworthy that even when expression of both arrestins 2 and 3 expression is inhibited, a weak proportion of DOR is able to internalize. This is in good agreement with data obtained by Aguila and collaborators who showed that inhibition of arrestin 2 expression reduces etorphine-induced hDOR endocytosis but not upon DPDPE or deltorphin I exposure Aguila et al. As demonstrated for MOR and DOR, KOR also undergoes an arrestin-dependent sequestration when activated by U50, as shown by the reduction of internalization when the dominant negative mutant arrestin 2 — is over-expressed Li et al.
Together, those data indicate that arrestins are key partners of OR internalization but under specific conditions or agonist exposure, other arrestin-independent mechanisms could occur. Arttamangkul and collaborators studied desensitization on potassium currents and internalization in neurons from locus coeruleus of transgenic mice expressing a FLAG-tagged MOR Arttamangkul et al. Three kinds of ligands can be identified: those which promote both desensitization and internalization [Met 5 ]-enkephalin, etorphine, and methadone , those which induce a desensitization without internalization morphine and oxymorphone and oxycodone which promote neither desensitization nor internalization.
This reveals the absence of any strong association between internalization and desensitization. In the Xenopus oocyte expression system, it is possible to observe an acute desensitization of DOR on potassium channels Kir3 elicited by DPDPE without significant internalization measured by surface biotinylation Celver et al.
When DOR internalization is significantly inhibited by over-expression of the dominant negative mutant of dynamin K44E , the desensitization promoted by sustained exposure to DPDPE is not altered Qiu et al. This is in good agreement with the observation of Marie et al. However, upon etorphine exposure a partial reduction of hDOR desensitization is measured when internalization is inhibited.
In contrast, the abolition of rKOR internalization by the SA substitution also inhibits receptor desensitization on potassium currents Mclaughlin et al. Those data demonstrate that desensitization and internalization are usually two independent processes although in some situations a close relationship could be evidenced. Those apparent discrepancies may be related to the different behavior of MOR and DOR in terms of trafficking see below.
For MOR, internalization would rather promotes recycling and resensitization; when blocking endocytosis, desensitization would be increased. In contrast, DOR are preferentially targeted to degradation, and inhibition of endocytosis would reduce their desensitization; however, this assumption assumes that the receptor at the plasma membrane is not uncoupled from G proteins and it's not always the case.
Once internalized, the OR can follow different routes: sequestration into endosomes, recycling back to the cell surface or targeting to degradation. The same group also identified a motif localized at the C terminal region of MOR that enables an active recycling Tanowitz and Von Zastrow, Arrestin 3, dynamin and GRK2 also participate to MOR resensitization on the activation of potassium channels in neurons from the locus coeruleus of mice treated during 6 days with morphine Dang et al.
This could suggest that those proteins would be involved in MOR trafficking after its internalization and that internalization itself contributes to resensitization Dang and Christie, Using neurons obtained from the locus coeruleus of transgenic mice expressing a FLAG-tagged MOR, chronic morphine but not methadone during 6 days was shown to inhibit resensitization and recycling after an acute [Met 5 ]-enkephalin exposure Quillinan et al.
Such weak resensitization and recycling return to the level observed in naive mice when arrestin 3 was knocked-down indicating that this protein would also play a pivotal role in MOR trafficking. The first hypothesis is unlikely since the sorting of the MOR either toward recycling or lysosomal degradation does not rely on receptor ubiquitination Hislop et al. The recycling process involves protein kinases as shown by staurosporine, which increases recycling and resensitization after [Met 5 ]-enkephalin exposure Arttamangkul et al.
Resensitization of MOR after [Met 5 ]-enkephalin- or morphine-induced acute desensitization but not cellular tolerance involves dephosphorylation mediated by protein phosphatases sensitive to calyculin A but not okadaic acid Levitt and Williams, The role of receptor dephosphorylation was also demonstrated for both recycling and resensitization of DOR after etorphine treatment Hasbi et al.
As indicated above, DOR was initially described as a receptor sorted to lysosomal degradation Tsao and Von Zastrow, This indicates that the differential sorting of DOR either to recycling or degradation pathway depends on the agonist used and refers to the notion of biased agonism.
Consequently, the receptor is mainly targeted to lysosome while upon DPDPE exposure, interactions between DOR and arrestin 3 are loose allowing receptor recycling. The ability of DOR to recycle also depends on the duration of agonist exposure. For instance, after 30 min of etorphine treatment, DOR recycles while after 4 h this process is severely impaired Hasbi et al. Zhang and collaborators showed different mechanisms to explain the differential sorting of DOR Zhang et al.
Recently, the endothelin converting enzyme-2, localized in endosomes, was shown to modulate recycling of DOR by degrading opioid peptides such as deltorphin II or the opioid peptide bovine adrenal medulla 22 BAM22 , a cleavage product of proenkephalin Gupta et al. When this enzyme is inhibited, DOR recycling decreases and consequently, the desensitization increases.
It is noteworthy that this enzyme is ineffective when DOR is activated by the endogenous peptide [Met 5 ]-enkephalin and has no role on receptor internalization.
The vast majority of studies on OR desensitization demonstrated that phosphorylation of OR constitutes a rapid and ubiquitous regulatory mechanisms. However, as illustrated for MOR, quantitative Lau et al. Conversely, some studies using phosphorylation-deficient receptor challenged this paradigm Qiu et al. OR phosphorylation should rather be viewed as a potentiating mechanism that would increase binding of regulatory proteins such as arrestins to the receptor.
Mechanisms of desensitization share common features phosphorylation, accessory proteins involvement such as arrestin, importance of endocytosis and receptor trafficking and will dependent not only on agonist biased agonism but also on time exposure, cell system and receptor.
All those mechanisms are depicted in Figures 2A,B. Figure 2. Schematic illustration of mechanisms involved in opioid receptor desensitization by biased agonists. However, MOR phosphorylation at S induced by morphine is able to promote desensitization but not internalization Schulz et al.
Some reports rather suggest that under morphine exposure, MOR is not desensitized and this continuous signaling promotes tolerance Finn and Whistler, Even if it's now well-admitted that morphine is able to promote MOR internalization Haberstock-Debic et al. MOR is dephosphorylated by phosphatase proteins Doll et al. Etorphine-induced desensitization requires arrestins but not receptor internalization.
Once sequestrated by etorphine, hDOR is dephosphorylated and recycled back to the cell surface Hasbi et al. Drug tolerance is the body's ability to protect itself against the presence of a drug.
Although the clinical relevance of this phenomenon during the perioperative period is somewhat controversial, several studies have demonstrated increased opioid requirements and worsened pain scores in patients exposed to high-dose intraoperative opioids.
The difference between acute opioid tolerance and OIH is conceptually easy to understand, but the two are clinically difficult to separate. OIH is defined as the increased sensitivity to painful stimuli as a result of opioid use.
Tolerance is defined as a requirement for increased doses of an opioid to achieve the same analgesic effect. In clinical practice, the development of either of these phenomena will lead to increased pain, with the usual consequence of escalating doses of opioids.
Whether the increased opioid requirement is caused by lowering the pain threshold, as in OIH, or by decreasing the potency of the drug, as in tolerance, the clinical effect is the same.
They appear to have a dose—response relation and as such the magnitude of tolerance or OIH in the setting of high-dose opiates is increased. The concept of OIH has been recognized for over yr. These include activation of adenylate cyclase, N -methyl- d -aspartate NMDA -type glutamate receptor activation, and release of pronociceptive peptides such as dynorphin A and neuropeptide FF.
According to this theory, the pronociceptive response is delayed or masked by analgesia after administration of an opioid but increases when repeated doses are administered. Hence, one initially expects to see analgesia in response to opioid administration, but increasing pain will develop with repeated doses. Six groups of rats were randomized to receive either subcutaneous saline injections or various doses of fentanyl.
Their pain threshold was determined at baseline using a paw-pressure vocalization test. They then received saline or fentanyl injections subcutaneously every 15 min for a total of four injections, and the pain threshold tests were repeated over the next few hours until evidence of analgesia disappeared.
The examiners then repeated the tests daily for the next 5 days. All rats that received fentanyl developed OIH meaning that on posttrial day 1, all rats had a decreased pain threshold from baseline.
OIH persisted much longer than the duration of analgesia, with the rats that received the highest dose of fentanyl demonstrating OIH for 5 days. No change in pain tolerance was observed in rats that received saline. This study not only demonstrates robust OIH development after opioid administration but also shows that it can develop within a very short time, comparable to the length of the perioperative period.
It is hard to extrapolate these data for human clinical use, but it serves as an illustration of the concept of OIH. Similar findings, however, have been confirmed in humans.
As mentioned, separating tolerance and hyperalgesia is difficult in the clinical setting. In addition, the type of pain that is aggravated wound hyperalgesia vs. It has been demonstrated that wound hyperalgesia the size of the area of hypersensitivity surrounding a wound specifically has an effect on long-term pain.
Salengros et al. After measuring the area of wound hyperalgesia, he showed that its size was increased by higher doses of IV opioids, and the extent of wound hyperalgesia corresponded to an increased risk of chronic pain at 3, 6, and 9 months. Guignard et al. Patients were randomized to receive either a high-dose or low-dose remifentanil infusion throughout the procedure; the remainder of the anesthetic was standardized.
On average, the patients receiving high-dose remifentanil receiving on average 0. This same phenomenon has been shown with remifentanil in children 12 and with fentanyl in adults. Several studies were unable to demonstrate evidence of OIH after intraoperative opioid administration. For example, in women undergoing gynecologic surgery, no difference was found in pain scores between groups receiving sevoflurane anesthesia versus sevoflurane and a remifentanil infusion.
In addition, the average dose of remifentanil was moderate and, therefore, would likely show a lower demonstrable effect of OIH. A recent meta-analysis of postoperative OIH by Fletcher and Martinez 25 took these negative studies into account and still demonstrated that high-dose approximately 0. This meta-analysis included 21 randomized, controlled trials of intraoperative remifentanil, most of which were published after The meta-analysis also included two studies of fentanyl and one of sufentanil.
These opioids did not seem to induce OIH, but obviously the data set is limited. It is reasonable to expect that all opioids would function in the same manner, activating pronociceptive systems, although in recombinant models remifentanil has been suggested to have additional actions, such as direct activation of NMDA receptors. There are also some limited data to suggest that intrathecal opioids can cause OIH 27 although much more study is needed to investigate that route of administration.
One study not included in the meta-analysis evaluated the use of remifentanil versus esmolol versus fentanyl during the laparoscopic cholecystectomy.
The remifentanil and fentanyl groups showed increased requirement for opioid in the postanesthesia care unit compared with the esmolol group. Postoperative fentanyl requirements were Patients receiving esmolol also were discharged from postanesthesia care unit earlier than patients receiving opioids. Although other explanations are possible e.
Postoperative opiate requirements in patients receiving esmolol, fentanyl, and remifentanil intraoperatively. Amounts of fentanyl required in the postoperative care unit PACU to provide adequate analgesia in patients who underwent laparoscopic cholecystectomy. The use of intraoperative opioids is associated with an increased postoperative opioid requirement. Modified from Collard et al. Anesth Analg ; — The best way to address OIH or acute tolerance will likely be prevention.
For this reason, it is prudent to consider alternative opioid-sparing adjuncts when possible, in an effort to reduce the opioid use for patients under general anesthesia. Peripheral nerve blocks and neuraxial anesthesia can reduce the need for opioids and have an opioid-sparing effect.
0コメント