“In the practice of tolerance, one’s enemy is the best teacher.”   –   14th Dalai Lama

Opioid Tolerance



It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:



Neurobiology of Opioids

Neurobiology of Pain

Neuropathic Pain

Opioid Tolerance

Opioid Induced Hyperalgesia (OIH)

Opioid Withdrawal

Withdrawal Induced Hyperalgesia (WIH)

TLR-4 Antagonists



Individual opioids:

Buprenorphine (for Pain)


Methadone (for Pain)

Tapentadol (Nucynta)



Definitions and Terms Related to Pain


Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication


Opioid Tolerance

Tolerance, in this case, is not actually the type of tolerance referred to by the Dalai Lama, but a medical term.

Tolerance refers to a normal neurobiological process characterized by the need to increase the dose of a medication over time to maintain the original effect. Tolerance is the result of the nervous system adapting to the effects of a medication, a process related to neural plasticity, or the nervous system’s ability to change. Some people build tolerance more quickly than others. Some medications develop tolerance more quickly than others.

The Importance of Understanding Opioid Tolerance

Tolerance to opioid effects is not fixed, it can change. This is true for tolerance to the nausea effects as well as analgesic effects and sedative and respiratory depression effects. If one is not aware of the variables that can alter one’s tolerance, the belief that “I have a high tolerance to opioids” can get someone into serious trouble.


Different Rates of Development of Different Opioid Tolerances

The process of tolerance develops at different rates for different effects and the tolerance profile is different for each opioid. Tolerance develops to both the desired benefits of a drug as well as to the undesired side effects of a drug.


Tolerance to Nausea

In general, tolerance to the side effects of nausea and vomiting associated with the use of opioids dissipates fairly quickly, usually measured in days. The use of anti-nausea medications (antiemetics) can usually suppress the nausea when starting a new opioid, allowing time for a person to develop tolerance and the nausea will go away.


Tolerance to Constipation

In some cases, such as opioid-induced constipation, tolerance develops very slowly or not at all so that despite taking the same opioid for weeks or months, the constipation associated with that particular opioid may never improve, necessitating a change to another opioid.


Tolerance to Analgesia (Pain Reduction)

Analgesic tolerance is generally what is referred to by the term “opioid tolerance.” It is a problem for those taking chronic opioids because over time the opioids may become less effective. The reduction of opioid analgesic benefit over time may also reflect the process of opioid-induced hyperalgesia (OIH) as well as the process of central sensitization along with opioid tolerance, together manifesting as a reduced effectiveness for pain. (See OIH and Neurobiology of Opioids).

See below for additional information regarding opioid analgesic tolerance

Tolerance to Sedation

In general, tolerance to the sedative (drowsiness) effects of opioids builds fairly quickly, usually measured in days, sometimes weeks. But because it does take time, it is important that when starting an opioid for the first time, or when increasing one’s dose, one be careful not to drive or operative dangerous machinery until one is certain that their performance will not be impaired.

Tolerance to Respiratory Depression

Respiratory depression is not the same as sedation, although related. Opioids all have the side effect of respiratory depression, or reduced depth and/or frequency of breathing. While this effect may be unnoticeable when one is awake, it is nevertheless measurable, but under usual circumstances it is not clincally important.


When respiratory depression from opioids becomes important is when one is asleep and has contributing conditions that can lead to accidental overdose death. When respiratory depression becomes severe enough it results in reduced oxygen and increase carbon dioxide in the blood which can trigger a heart attack while asleep. When the opioid blood level become excessive, it results in cessation of breathing, which is the cause of death in opioid and other sedative overdoses.


Fortunately, when people use opioids chronically they develop significant tolerance to their respiratory depression effects and over time can tolerate very high doses of opioids without experiencing overdose. When dosing of opioids is increased very slowly the individual when usually adapt to the higher doses by developing tolerance. But if dosing increases too quickly one becomes susceptible to opioid overdose.


When the unexpected opioid overdose can occur

Put simply, opioid overdose occurs when the dose of an opioid exceeds a person’s tolerance for that opioid. While the term “overdose” can be applied to any circumstance in which a dose causes significant side effects such as slurred speech, impaired judgement or excessive drowsiness, “overdose” usually refers to the fatal overdose. Learning about how a person’s tolerance may be unexpectedly inadequate to avoid accidental death is the most important teaching point in pain management. Relying on “common sense,” while usually adequate to avoid dangerous overdoses, may not always be enough. So here are some considerations to be aware of.


Tolerance to the euphoric, or “feel-good” effect to opioids develops more quickly than tolerance to respiratory depression

While the vast majority of those taking opioids do so strictly to relieve pain, some people fall victim to taking opioids to improve their mood and experience the euphoric effects of their opioids. When doing so, the person who chases the euphoric effect will need to continue to increase their dosing fairly rapidly due to the fact that tolerance to the euphoria develops more quickly than the tolerance to respiratory depression.  This is often the mechanism by which those who use opioids for the wrong reason accidentally die.


Tolerance to the analgesic, or pain relieving benefit of opioids may develop more quickly than tolerance to respiratory depression

In most cases with the opioid management of chronic pain, patients develop safe levels of tolerance to opioid-induced respiratory depression while at the same time they experience good analgesic benefit, so that the use of chronic opioids for pain is both safe and effective. But sometimes the analgesic benefit of an opioid lags behind the respiratory depression tolerance to that opioid, leading to an overdose when one too rapidly increase their opioid dose seeking greater pain benefit.


This is a frequently encountered circumstance when a patient who previously tolerated high doses of opioids experiences a major reduction or discontinuation of their high doses for a period of time due to running out of medications, losing their physician or other access to their usual medications. The longer the period of time at reduced or absent opioid doses, the greater their tolerance to respiratory depression wears off, often faster than the pain benefit. If this person restarts their previous high dose suddenly, for example, when they regain access to their opioids, they may accidentally overdose. This may be particularly true for morphine (and heroin) as well as methadone. While a number of variable come into play under these circumstances, the complexity of predicting safe dosing argues for maintaining a slow, conservative regimen of restarting and increasing the doses of opioids.


The lesson to be learned here is that whenever starting, or re-starting, opioids: “Start low, Go slow.”


Alcohol can reverse tolerance

Another variable is the use of alcohol. Alcohol can quickly reverse an established tolerance to opioid respiratory depression, thus making the person more susceptible to overdose even when the amount of alcohol itself may not appear excessive on its own. In the evaluation of opioid overdose deaths, the blood levels of opioids are significantly less, on average, when alcohol is also present. Diazepam (Valium) has also been shown to reverse tolerance to opioid respiratory depression.


This effect of alcohol varies depending on the opioid, but morphine (and heroin) appear particularly sensitive to this potential for accidental overdose. This property of alcohol (and diazepam/Valium) accompanied by its own contribution to respiratory depression is one of the reasons why accidental opioid overdoses are frequently associated with co-use of alcohol (and diazepam/Valium).


Recent research has also shown that in addition to alcohol, both gabapentin (Neurontin) and pregabilin (Lyrica) also reduce tolerance to morphine and oxycodone. This reversal of tolerance affects both analgesic tolerance as well as respiratory tolerance. It appears also that the extent of this tolerance reversal may depend on the efficacy of the opioid (see above). Methadone, an opioid with high efficacy does not appear to be as affected by alcohol or pregabalin tolerance as do oxycodone and morphine which have low efficacy. How clinically meaningful these distinctions are is not known.


In the last few years there is growing recognition that gabapentin and pregabalin are being abused by people, usually when used in combination with opioids. For example, heroin users report that pregabalin reinforces or enhances the rewarding effects of heroin which likely represents the results of opioid tolerance reversal by these drugs. Unfortunately, this enhancement of the rewarding effect of heroin use is accompanied by enhancement of the respiratory depression effect of heroin, thus leading to increased susceptibility for accidental overdose death. In fact, in recent years in England and Wales, there has been a dramatic increase in acute drug deaths involving pregabalin and gabapentin. In 2016  over 90% of deaths in which pregabalin or gabapentin was present at post mortem, an opioid was also present (Office for National Statistics, 2017).




For the purpose of convenience, unless otherwise specified, the use of the term “tolerance” refers to “analgesic tolerance.”

Cross-Tolerance Between Opioids

Another important concept to understand is that of “cross tolerance.” When changing, or “rotating,” from one opioid to another opioid, the development of tolerance to the first opioid will likely also create tolerance to the second opioid as well, called “cross-tolerance.” But this cross-tolerance is usually incomplete, meaning that the tolerance to the second opioid is not likely to be as high as to the first opioid that a person has been taking for awhile. Thus when rotating to a second, new opioid, a patient may get better pain response with the second opioid even when taken at a dose considered “equivalent” to the first opioid. This is a case in which cross-tolerance (analgesic) works in favor of the patient.


However, in the case of the sedative and respiratory depression effects of opioids, incomplete cross tolerance can be dangerous. When rotating to a new opioid, consideration must be given to the possibility of incomplete cross tolerance to the sedative and respiratory depression effects. If there is increased sensitivity to the sedative and respiratory depressive effects, there is a potential for accidental over-sedation or overdose.


Because of concerns related to cross tolerance, when a patient is changed to a different opioid the physician will adjust the dosage of the new opioid to accomodate for the incomplete cross-tolerance both to the analgesic benefit but also to the risk of respiratory depression and potential overdose. Failure to do so can result in bad outcomes.

Unilateral Cross Tolerance

Of particular interest regarding incomplete analgesic tolerance between two opioids is that it doesn’t necessarily work the same going from opioid 1 to opioid 2 as it does going from opioid 2 to opioid 1. For example, one study found that pretreatment with levorphanol resulted in tolerance to morphine but pretreatment with morphine resulted in less tolerance to levorphanol (levorphanol was more effective than one be expected if tolerance worked the same going both directions). One explanation is that levorphanol works on both the mu opioid receptor and the kappa opioid receptor (K-3) to reduce pain, whereas morphine only works on the mu opioid receptor. Opioid cross tolerance does not extend between the different opioid receptors (mu vs delta vs kappa opioid receptors). (see Neurobiology of Opioids). Thus, when rotating between these two meds, it may be more effective changing from morphine to levorphanol than vice-versa.


Another possible explanation is that levorphanol reverses the analgesic tolerance resulting from prolonged morphine use. A recent study (on mice) published in 2015 showed that when the animals were pre-treated with morphine and built up analgesic tolerance, giving methadone or fentanyl reversed the tolerance to morphine while oxycodone did not. While levorphanol was not evaluated in this study, given some of the characteristics of levorphanol that overlap with fentanyl and methadone, it may well also be that it works the same way to reverse opioid tolerance derived from prolonged morphine use.


Another study showed that pretreatment with methadone resulted in tolerance to morphine and codeine but pretreatment with morphine did not result in the same degree of tolerance to methadone. In this case, the unilateral cross tolerance may also be due to the NMDA antagonist analgesic benefit of methadone that does not occur with morphine (see Neurobiology of Opioids). Tolerance to the mu-opioid related analgesia works both ways while their is no cross tolerance from mu-opioid activity to the NMDA receptors.


While additional studies are warranted, this does suggest the benefit of rotating from morphine to methadone or fentanyl periodically to regain analgesic benefits of morphine.

While these studies are interesting, predicting the degree of cross tolerance for an individual is not possible. There are  substantial individual variations in opioid tolerance and cross tolerance due to indivdual differences in medication metabolism and response. But understanding cross tolerance variables can allow for better choices when rotating between opioids when indicated.

The Effect of Pain on Tolerance

Pain antagonizes the sedative and respiratory depressive effects of opioids by stimulating the brain and increasing alertness. Caution should be applied when a patient taking high opioid doses suddenly experiences a significant reduction in their pain as might occur after an interventional pain procedure or surgery. Removing the stimulating effect of pain leaves the respiratory depressive effect of the opioid unopposed, placing the patient at greater risk for over-sedation or respiratory depression/overdose. For this reason, after a successful procedure resulting in reduced pain, it is important to reduce the opioid dosing proportionately to the pain to avoid complications.


The Rate of Development of Analgesic Tolerance

Intermittent Dosing vs. Extended Release Dosing

Studies show that the development of tolerance using intermittent dosing is  significantly slower when compared with extended release dosing or constant infusions. While there are other arguments relative to the benefits of short-acting vs. extended release opioids, this argument suggest that short-acting opioids may be advantageous.


Differences in the Development of Tolerance Between Individual People

However, the rate of development of analgesic tolerance to individual opioids varies from individual to individual and also from one opioid to another opioid. It is not well understood why some patients develop tolerance more quickly than others and there are no clinically useful theories forthcoming at this time. While an individual’s genetics likely play a role, there is little to no research available to identify individuals at risk for accelerated tolerance to individual opioids or opioids in general. In fact, Dr. Ehlenberger is preparing a study at Accurate Clinic to investigate this question.


Differences in the Development of Tolerance Between Different Opiods

There is some recent research that suggests that tolerance to some individual opioids develops faster than others. While there may be individual patient variation of analgesic tolerance development that could be influential, the following is a list of opioids and their relative speed of development of analgesic tolerance:


Tolerance Develops Quickly  

Oxycodone (fastest)

Oxymorphone (Opana)

Hydromorphone (Dilaudid, Exalgo)


Hydrocodone (Norco, Lortab, Vicodin)


Fentanyl (Slowest)

Tolerance Develops Slowly

It should be noted that this list reflects tolerance (not potency).  The list is based on measured values of each opioid’s “intrinsic efficacy” for the mu-opioid receptor (see below) and does not take into account  opioids with NMDA antagonist activity which is known to reduce tolerance. Nor does this list reflect opioids with SNRI or NRI activity (see Neurobiology of Opioids), another variable that is likely to affect tolerance. Finally, it does not take into account other mechanisms that contribute to the development of tolerance such as neuroinflammation and genetic variants that impact an individual’s response to opioids.

(See: Neurobiology of Opioids)

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Opioids with NMDA antagonism activity include methadone, buprenorphine and levorphanol. Due to the fact that NMDA antagonism reduces opioid tolerance, these three opioids are likely to develop tolerance more slowly than predicted based only on their intrinsic efficacy for the mu-opioid receptor.

See: Methadone – Tolerance


Opioids which have SNRI or NRI activity include tramadol, tapentadol, levorphanol and buprenorphine. The presence of SNRI or NRI activity enhance an opioid’s analgesic benefits and is also likely to slow the development of tolerance. (See Neurobiology of Pain)


The following is a list of opioids with NMDA and/or SNRI or NRI activity and analgesic benefits that comes from mechanisms other than the opioid receptors and therefore are likely to develop tolerance more slowly:


Tramadol (SNRI)

Tapentadol (NRI)

Buprenorphine (SNRI & NMDA antagonism)

Methadone (SNRI & NMDA antagonism)

Levorphanol (SNRI & NMDA antagonism)


Unfortunately, no head-to-head, long term studies are available that actually look at comparing tolerance with one opioid compared to another over a span of years of treatment. Physicians prescribing these opioids long term no doubt have their opinions, but it is unlikely there would be a clear consensus of opinion along these lines.


Does analgesic tolerance always continue, or does it stabilize over time?

Unfortunately, this question has not been definitively answered but evidence suggests that there is a “ceiling” to analgesic tolerance in which the magnitude of tolerance levels out.


The Prevention and Treatment of Opioid Analgesic Tolerance (OAT)

There are multiple mechanisms (see below) that contribute to opioid analgesic tolerance (OAT) that vary with individual opioids which makes understanding and treating OAT complex and difficult. While insufficient clinical research is available to definitively treat OAT, there are potential treatments available. The most common and direct treatment approach is to rotate to a different opioid if confronted with opioid tolerance, when simply increasing the dose of the opioid is not desired. “Opioid Rotation” is a common approach to treating tolerance by taking advantage of incomplete cross tolerance. As noted above, rotating to an opioid with a different profile of analgesic benefit would likely be effective, i.e. taking into account different opioid’s NMDA antagonism and opioid receptor activity and SNRI activity (See Neurobiology of Opioids).


NMDA Antagonists

Alternatively, the use of other NMDA antagonists such as dextromethorphan or ketamine may be effective in preventing and/or reducing opioid tolerance (See OIH). Methadone, which has some NMDA antagonist activity, has been shown to reverse morphine-induced analgesic tolerance. While the NMDA antagonist action may play a role in this benefit, other mechanisms have recently been identified to explain this significant finding. A course of methadone treatment may be very effective in re-establishing pain control by rotating from morphine to methadone.


Kappa Opioid Receptor Antagonists

Recent research has identified the role of kappa opioid receptor stimulation in the development of opioid analgesic tolerance and opioid hyperalgesia. Buprenorphine has been found to antagonize the action of opioids such as morphine on the kappa receptors and reverse or block analgesic tolerance and opioid hyperalgesia. This is one of the stronger arguments for the use of buprenorphine when encountering a situation of inadequate pain control related t
o increased analgesic tolerance to such opioids as oxycodone, hydrocodone or morphine.


Epigenetics and 5-HT3 Receptor Antagonists (Ondansetron (Zofran)

Research over the last few years has discovered a significant role for epigenetics, or the modulation of DNA and genes, that impact biochemical processes associated with the evolution of opioid tolerance and opioid hyperalgesia. By blocking the activity of these genes it may be possible to block or reduce these conditions established by chronic use of opioids. Early studies have suggested that ondansetron (Zofran) may be effective in this regard. Ondansetron, a 5-HT3 receptor antagonist, has been used effectively in the treatment for nausea and vomiting and other symptoms related to opioid withdrawal.



Gabapentin (Neurontin) has been shown to suppress microglial activation, suggesting this as a mechanism not just for its benefit in reducing neuropathic pain but also as a potential means of reducing opioid tolerance.

See: Gabapentin (Neurontin) & Pregabalin (Lyrica)


CAM Options

Given the role of inflammation and free radicals in opioid tolerance, another approach that offers potential benefit for the prevention or reduction of tolerance is to supplement with antioxidants and/or NRF2 activators to reduce the  oxidative stress that may be associated with tolerance and hyperalgesia. Evidence is present for the benefit of omega-3, curcumin and resveratrol, two well-studied antioxidants and NFR2 activators. Early research suggests that minocycline and palmitoylethanolamide (PEA) may offer benefit. (See below).


The Neurobiology of Opioid Tolerance

Multiple mechanisms for the development of opioid tolerance have been proposed. Classical neuron-centered concepts about tolerance include opioid receptor desensitization and internalization of opioid receptors. With continued exposure to an opioid, the opioid receptors present on the surface of a cell go through a process of internalization in which the surface opioid receptors get absorbed into the cell membrane internally where they are no longer available to the opioid, thereby reducing the ability of the opioid to impact its receptor-triggered response. Uupregulation of N-methyl-D-aspartate (NMDA) receptor function is another mechanism proposed for the development of OAT as well as downregulation of glutamate transporter activity, but these proposed mechanisms can only partially explain the phenomenon of tolerance. Recent research has identified the role of neuroinflammation as another contributing mechanism for OAT. These mechanisms are explored flurther below.


Opioid Receptor Densensitization and Internalization

Opioid activation of neuronal mu opioid receptors (MORs) increases potassium conductance into the nerve cell, transmitting an effect response. This receptor/effect response characterizes the acute and chronic actions of opioids. Chronic treatment with opioids results in a decrease in mu-opioid receptor sensitivity, or desensitization, in which there is shift in the concentration  of opioid needed to elicit a response to opioids and a decrease in the maximum response induced by opioids.


Another mechanism of opioid tolerance occurs when, after continued exposure to opioids, the opioid receptor on the exterior of the nerve cell internalizes and is no longer available for stimulation by opioids in the nerve’s environment. The greater degree of internalization of opioid receptors, the fewer receptors are available to allow for an effect response from treatment with opioids.


After reduced or termination of opioid exposure, opioid receptor function recovers, with a return toward baseline levels of receptor sensitivity and reversal of the internalization of the receptors. How different opioids differ in the degree to which they induce receptor sensitivity and how quickly that sensitivity recovers is not well understood. Morphine, for example, differs from methadone in which there is reduced recovery from desensitization and receptor recycling compared with methadone.


Desensitization is dependent on receptor phosphorylation by a G protein receptor kinase (GRK), an enzyme that facilitates binding of agents (β-arrestin, AP-2 and clathrin) that result in the internalizing of this receptor complex. Different opioids may have different degrees of effect on this enzyme contributing to differences in the development of tolerance. β-arrestin has also been implicated in the development of analgesic tolerance to cannabinoids. Medications that impact β-arrestin may offer future means of reducing the develo
pment of tolerance. 


Efficacy, Affinity and Potency

Factors that may impact internalization of opioid receptors may include the efficacy, affinity and potency of the opioid. Evidence points to the rate of development of tolerance to be dependent on the “intrinsic efficacy” of an opioid, (a measurable quality) which is defined as “the relative ability of agonists to produce a response for a given receptor occupancy.“ Intrinsic efficacy is a property solely of the drug-receptor complex and, theoretically, is independent of the cellular environment. While similar, it is different from a measure of an opioid’s potency, or strength of effect. In addition, the ability of an opioid to develop tolerance appears to be inversely related to its effectiveness to internalize and downregulate μ-opioid receptors. Intrinsic efficacy must be distinguished from “affinity,” which is a measure of the ability of the drug to bind to its molecular target, and the EC50 (half maximal effective concentration), which is a measure of the potency of the drug. Ultimately, the potency of an opioid is proportional to both efficacy and affinity. (Got it?)


Opioid and NMDA Receptors and Tolerance

As discussed in the “Neurobiology of Opioids, opioids interact with structures on nerve cell membranes called receptors and this interaction is what leads to their pharmacologic effects.  Different opioid receptors interact with one another and triggering an opioid receptor can stimulate biochemical reactions (adenyl cyclase and cAMP) that can contribute to the evolution of tolerance.  Interaction between opioid and NMDA receptors appears to contribute to opioid tolerance also.  It has been demonstrated that blocking the activity of NMDA receptors with NMDA antagonists may reduce or reverse opioid tolerance.

Glial Cells, Inflammation and Free Radicals Contribute to Opioid Tolerance

Research over the last 15 years has identified additional mechanisms of opioid tolerance. Immune cells, (glial cells), in the structural matrix of the cellular environment surrounding nerve cells in the peripheral and central nervous system have been found to contribute to tolerance. Damage related to injured nerve cells triggers a response by these glial cells,  resulting in the release of inflammatory chemicals that ultimately contribute to opioid tolerance and hyperalgesia. It has been shown that the creation of free radicals including superoxide and nitric oxide plays a role in opioid tolerance and hyperalgesia.


The search is on for medications that can safely and effectively suppress the microglial activation that contributes to opioid tolerance and hyperalgesia. Early, preclinical animal research suggests that gabapentin (Neurontin) may play such a role, suggesting yet another beneficial role for this medication in managing chronic pain. Researchers have apparently not explored whether pregabalin (Lyrica) offers similar potential benefits.



Palmitoylethanolamide (PEA)

Gabapentin (Neurontin) & Pregabalin (Lyrica)



Other Factors That May Contribute to the Appearance of Tolerance

When an opioid begins to lose its apparent effectivenss there may be other factors at play besides opioid analgesic tolerance (OAT). Besides the obvious, that either the painful condition has worsened or other variables are increasing the pain such that it appears that the opioid is not working as well as expected, another factor is whether the blood levels of the opioid have changed.  There are a few things to consider:


The opioid medication itself is less potent

Not all medications are manufactured equivalently. Governmen standards allow for 80-125% variability in the manufacturing process as to the measured content of the medication. It has been established that not all generic medications are equivalent. Furthermore, while the full extent is not known, there are growing reports of counterfeit medications being substituted in the market place. While this is a much larger problem in the world of illicit drugs and medications, it is not unheard of in the commercial market (see Counterfeit Medications).


The opioid absorption from the gut is altered

While this
is not a variable likely to change suddenly, exacerbations of inflammatory bowel conditions may alter absorption of the medication, especially with time-release medications, causing blood levels to go down. Alcohol can have the opposite effect by accelerating the breakdown of time release medications and causing blood levels to rise abruptly.


The metabolism of the opioid may be altered

A common, overlooked occurence is related to drug-drug, drug-herb and drug-food interactions that change how an opioid is metabolized. This can result in significant fluctuations of the blood level of an opioid medication despite maintaining a steady, routine dose. While it is beyond the scope of this page to explore this topic in detail, it should be emphasized that adding a new medication, health supplement or even a food or juice can markedly impact the blood level and the therapeutic effect of a stable opioid regimen. Based on an individual’s genetic background one can be particularly susceptible to this type of occurence. In addition, some medications are more susceptible to this as well, especially methadone.





Opioid Tolerance – Overviews

  1. Opioid Tolerance – the Clinical Perspective
  2. The effect of intrinsic efficacy on opioid tolerance. – 1995
  3. Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of μ-opioid receptors and dynamin-2 – 2007
  4. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human – 2011
  5. Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat – 2012
  6. Change in functional selectivity of morphine with the development of antinociceptive tolerance – 2014
  7. In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression – no two opioids have the same profile – 2014
  8. Mu-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons – 2013
  9. Hydromorphone efficacy and treatment protocol impact on tolerance and μ-opioid receptor regulation – 2008
  10. regulation-of-%c2%b5-opioid-receptors-desensitization-phosphorylation-internalization-and-tolerance-2013
  11. functional-selectivity-at-the-%ce%bc-opioid-receptor-implications-for-understanding-opioid-analgesia-and-tolerance-2011
  12. development-of-tolerance-and-sensitization-to-different-opioid-agonists-in-rats-2006
  13. opioid-receptor-desensitization-mechanisms-and-its-link-to-tolerance-2014
  14. opioid-tolerance-development-a-pharmacokineticpharmacodynamic-perspective-2008
  15. [Difference in tolerance to anti-hyperalgesic effect and its molecular mechanisms between chronic treatment with morphine, fentanyl and oxycodone i… – PubMed – NCBI
  16. Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation – 2016
  17. The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance – 2018
  18. Beta-arrestin-2 regulates cannabinoid CB1 receptor signaling and adaptation in a CNS region-dependent manner – 2012



  1. ethanol-reversal-of-tolerance-to-the-respiratory-depressant-effects-of-mo
  2. reversal-of-morphine-analgesic-tolerance-by-ethanol-in-the-mouse-2013
  3. ethanol-reversal-of-cellular-tolerance-to-morphine-in-rat-locus-coeruleus-neurons-2013



  1. Methadone tolerance testing in drug misusers – 2006
  2. Opioid tolerance in methadone maintenance treatment – comparison of methadone and levomethadone in long-term treatment – 2016
  3. methadone-reverses-analgesic-tolerance-induced-by-morphine-pretreatment-2015
  4. recovery-from-mu-opioid-receptor-desensitization-following-chronic-treatment-with-morphine-and-methadone-2011
  5. an-opiate-cocktail-that-reduces-morphine-tolerance-and-dependence-2005
  6. Characterization of methadone as a b-arrestin-biased k-opioid receptor agonist – 2016

Opioids – Individual

Opioids – Buprenorphine (Butrans, Belbuca, Suboxone, Subutex, Zubsolv, Bunavail)

Opioids – Fentanyl (Duragesic)

Opioids – Hydrocodone (Norco, Vicodin)

Opioids – Hydromorphone (Dilaudid, Exalgo)

Opioids – Levorphanol

Opioids – Methadone

Opioids – Oxycodone (Percocet, Oxycontin)

Opioids – Morphine (MSIR, MSER, MSContin)

Opioids – Tapentadol (Nucynta)

Opioids – Tramadol (Ultram, Ultracet)

Opioid Tolerance – Epigenetics

  1. 5-hydroxytryptamine-type-3-receptor-modulates-opioid-induced-hyperalgesia-and-tolerance-in-mice
  2. epigenetic-regulation-of-spinal-cord-gene-expression-controls-opioid-induced-hyperalgesia-2014
  3. epigenetic-regulation-of-opioid-induced-hyperalgesia-dependence-and-tolerance-in-mice-2013

Opioid Tolerance: Gabapentin

  1. Gabapentin reverses microglial activation in the spinal cord of streptozotocin- induced diabetic rats – 2009
  2. Gabapentin Blocks and Reverses Antinociceptive Morphine Tolerance in the Rat Paw-pressure and Tail-flick Tests – 2003
  3. The Effects of Gabapentin on Acute Opioid Tolerance to Remifentanil Under Sevoflurane Anesthesia in Rats – 2012
  4. Oxycodone-induced tolerance to respiratory depression – reversal by ethanol, pregabalin and protein kinase C inhibition – 2018

Opioid Tolerance – Microglia and Central Inflammation

  1. Opioid-induced Central Immune Signaling – Implications for Opioid Analgesia – 2015
  2. Microglia in the spinal cord and neuropathic pain – 2016
  3. Modulation of microglia can attenuate neuropathic pain symptoms and enhance mor
    phine effectiveness – 2008

Opioid Tolerance – Ondansetron (Zofran) / 5HT3 Antagonists

  1. ondansetron-a-review-of-its-pharmacology-and-preliminary-clinical-findings-in-novel-applications-pubmed-ncbi
  2. 5-hydroxytryptamine-type-3-receptor-modulates-opioid-induced-hyperalgesia-and-tolerance-in-mice
  3. epigenetic-regulation-of-spinal-cord-gene-expression-controls-opioid-induced-hyperalgesia-2014
  4. epigenetic-regulation-of-opioid-induced-hyperalgesia-dependence-and-tolerance-in-mice-2013
  5. the-5-ht3b-subunit-affects-high-potency-inhibition-of-5-ht3-receptors-by-morphine-2012
  6. agonist-and-antagonist-induced-up-regulation-of-surface-5-ht3a-receptors-2015
  7. the-5-ht3b-subunit-affects-high-potency-inhibition-of-5-ht3-receptors-by-morphine-2012
  8. prevention-by-the-5-ht3-receptor-antagonist-ondansetron-of-morphine-dependence-and-tolerance-in-the-rat-1996
  9. prevention-of-morphine-discontinuation-phenomenon-in-mice-by-ondansetron-a-selective-5-ht3-antagonist-pubmed-ncbi

Opioid Tolerance – Antioxidants and NRF2 Activators

Opioid Tolerance – Curcumin

  1. Curcumin attenuates opioid tolerance and dependence by inhibiting Ca2+:calmodulin-dependent protein kinase II α activity. – PubMed – NCBI – 2015
  2. Orally Administered Nano-curcumin to Attenuate Morphine Tolerance – 2013

Opioid Tolerance – Omega-3

  1. Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids – 2017


Opioid Tolerance – Resveratrol

  1. Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. – PubMed – NCBI

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


Supplements recommended by Dr. Ehlenberger may be purchased commercially online or at Accurate Clinic.

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

Accurate Supplement Prices