Opiate tolerance how fast

You can read below to learn more about when to consider an opioid taper, withdrawal symptoms and information on tapering.

There is no hard and fast rule on how much and how fast to taper your opioids. Some patients may require even slower tapers and it may take several weeks to months before you are completely tapered off of your opioids.

That is normal. Talk to your doctor, nurse practitioner or pharmacist before starting your taper to determine what pace is right for you. If you take opioids for more than a week, you may become dependent on them. This is not the same as being addicted.

It means that if you stop using opioids suddenly, you may have very uncomfortable, though not life-threatening, withdrawal symptoms. First, at baseline i. However, it cannot be ruled out that some of these patients were prone to develop chronic pain and that their increased pain was a reflection of an underlying sensitivity, rather than hyperalgesia.

Second, morphine induced no analgesia in these patients, even at very high plasma concentrations. In other words, the patients were completely tolerant to the analgesic effects of morphine, but only partially tolerant to the respiratory depressant effects of the drug.

Therefore, although more data in humans are required, differential opioid tolerance is appears to be a clinically relevant phenomenon. Patients using chronic opioids are often profoundly tolerant to analgesic actions of the drugs and will require increased doses of opioids to provide adequate postoperative analgesia.

However, only limited tolerance to the respiratory side effects of opioids has developed in these patients. They are, therefore, at increased risk for respiratory depression. To prevent adverse outcomes postoperatively, these patients require close monitoring after surgery. Providing supplemental oxygen may prevent hypoxia when ventilation is depressed but also will prevent any protective effect of the HVR, which is increased in patients receiving chronic opioids.

Supplemental oxygen will also reduce the usefulness of Sa o 2 monitoring. In addition to the concerns associated with differential tolerance to opioids, clinicians also need to consider the development of OIH in their patients. 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. In addition, although usually expensive, drugs such as esmolol 28 and dexmedetomidine 29 can approximate the effect of opioids on heart rate, blood pressure control, and volatile anesthetic requirement.

However, many patients will still require opioids perioperatively, and occasionally, chronically. The data available on differential opioid tolerance and OIH, although not absolutely conclusive for the perioperative setting, suggest that it would be prudent to craft an anesthetic that incorporates nonopioid adjuncts and not solely depend on intraoperative opioids for the provision of postoperative pain relief.

Patients using very high doses of opioid analgesics preoperatively may not be protected from adverse events by tolerance development, and this group may be at particular risk. Perioperative opioid administration may render subsequent opioid analgesic administration less effective and might lead to OIH or acute tolerance.

Still, many patients will undergo surgery of such magnitude that opioids will be required for postoperative pain control. 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. It is generally observed after protracted exposure but also after acute treatment acute tolerance and it is not observed for all the pharmacological effects.

For opioids, tolerance to analgesia has been primarily studied as it is the main issue in clinical practice. In rodent, the ability of opioid to promote analgesia to different type of stimuli could be measured using numerous behavioral paradigms including hot-plate test and tail-flick for thermal nociception Barrot, Different parameters could modulate tolerance such as the opioid agonist used Enquist et al.

So, it is now established that tolerance to respiratory depression is lower than the tolerance to analgesia Mohammed et al. Mechanisms of opioid tolerance are complex and multifaceted. We will focus on the mechanisms directly related to receptor regulation such as down-regulation, G protein uncoupling, desensitization, and internalization.

Down-regulation is the reduction of receptor number that may result from receptor internalization followed by their degradation, or decrease in receptor synthesis. So, one could hypothesize that it would contribute to tolerance by diminishing the quantity of available receptor. In vivo , chronic treatment with opioids promotes decrease down-regulation , no change or increase up-regulation of OR Bernstein and Welch, ; Stafford et al.

When downregulation is observed, tolerance might be measured Gomes et al. These data suggest that downregulation is not mandatory for tolerance. Desensitization and tolerance are very similar in their definition as they both include the notion of a reduced response after prolonged treatment. So, it is tempting to speculate that desensitization and its mechanisms would occur in tolerant animals.

In chronic morphine-treated animals desensitization of OR was measured on ACase Noble and Cox, and associated with tolerance to analgesic effects Polastron et al. In cellular model, receptor uncoupling from G proteins was demonstrated to participate in desensitization see above.

Such uncoupling was also evidenced in vivo after chronic opioid agonist exposure. Acute and chronic treatment with morphine or fentanyl promotes a similar regulation of MOR.

When arrestin 3 was knocked-out, morphine tolerance and MOR uncoupling from G proteins was reduced in chronic treated animals Bohn et al. Interestingly, this KO did not affect tolerance induced by 5 days treatment with fentanyl, oxycodone or methadone Raehal et al. Whereas in vitro experiments showed that S is phosphorylated by GRK5 upon morphine exposure Doll et al.

This could indicate that MOR desensitization and tolerance are two unrelated mechanisms. Similar results were obtained in GRK3 KO mice, when morphine tolerance to analgesia was unchanged whereas tolerance to high efficacy agonists, such as fentanyl or U50,, was reduced Terman et al.

Rather than inducing desensitization, a chronic morphine treatment could promote a compensatory increase in intracellular cAMP level also named cAMP overshoot or ACase superactivation Avidor-Reiss et al.

Accumulating evidences suggest that OR endocytosis decrease opioid tolerance but by mechanisms not fully understood. The first hypothesis has been built by Whistler's group on the inability of morphine to promote MOR internalization despite its capacity to induce strong tolerance. In line with this hypothesis, a knock-in mice, expressing a MOR chimera where the C-terminus tail was replaced by the C-terminus tail of DOR, demonstrated less tolerance after chronic morphine treatment Kim et al.

One explanation of this result is the termination of signal transduction because the DOR C-terminus tail will target the chimeric MOR to lysosomes Finn and Whistler, Such results were confirmed when comparing other opioid agonist, buprenorphine and etonitazene.

Indeed, buprenorphine, like morphine induces tolerance to analgesia without promoting MOR endocytosis, whereas etonitazene promotes less tolerance and has the ability to promote MOR internalization Grecksch et al. Interestingly, coadministration of morphine with subactive doses of internalizing opioids, DAMGO or methadone, enables morphine-induced internalization of MOR and blocks tolerance development He and Whistler, An alternative hypothesis was proposed by Koch and collaborators.

They proposed that morphine promotes an accumulation of desensitized MOR at the plasma membrane that would result in an increase in apparent desensitization by inhibiting resensitization and would promote tolerance Koch et al.

However, they found that in knock-in mice expressing MOR mutant SA substitution, proposed by these authors to be the primary site of morphine-induced phosphorylation of MOR responsible for desensitization Schulz et al. The RAVE relative activity vs. Interestingly, no tolerance for locomotor effects or anxiolysis appears in ARMtreated animals underlying the fact that biased agonist could be used at the behavioral level.

All those data support the role of internalization and mainly recycling in reducing tolerance by allowing a sufficient quantity of functional receptors at the cell surface to produce the biological response. However, some opioid agonists such as herkinorin can promote a long lasting anti-nociception without internalization due to the absence of arrestin 3 recruitment Lamb et al.

All the data presented in this review demonstrated that mechanisms of OR regulation are consistent with the model proposed by Lefkowitz Pierce et al.

More interestingly, they also showed that many variations around this model exist depending on the initial conditions, revealing the complexity of OR regulation now translated to the concept of biased agonism. It's an exciting challenge to gain insight this complexity because it will offer a great opportunity to design new drugs that will be able to target a particular pharmacological effect with limited side effects.

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