Tolerance to Opioid Pain Medications

Patients with chronic pain, their healthcare providers, and society, more generally, are all typically concerned about addiction to opioid pain medications. This concern is well founded. Once commonly thought of as rare,1, 2 it is now generally accepted that the true rate of addiction to such medications is much higher than what was once thought.3, 4 The issue of addiction to prescription opioid pain medications generates considerable debate among the stakeholders in the field of chronic pain management. There are strong voices for the continued use of such medications despite the rate of addiction and strong voices against the continued use of these medications because of the rate of addiction.

Whatever side we might take in this debate, there is another issue with which we should also concern ourselves. It’s the issue of tolerance to opioid pain medications. As a field, we do not discuss it nearly as much as we do addiction. Nonetheless, in its own way, tolerance too is problematic for those who manage chronic pain with the long-term use of opioid medications.

Definition of opioid tolerance

In general, tolerance to a drug is a phenomenon that occurs when an individual over time requires greater amounts of a drug to continue to obtain the original degree of its desired, therapeutic effect.5

When it comes to taking opioid medications for pain on a long-term basis, the issue of tolerance occurs in something like the following trajectory. When patients first start to take opioid medications for pain, they tend to need a minimal number of short-acting opioid tablets each day to reduce their pain. Over time, however, they notice that the one or two tablets no longer work as well as they once did and to obtain the previous level of pain relief they need to take three tablets or four tablets. At some point, down the line, their healthcare providers might become concerned about the increasing number of short-acting opioid tablets needed to relieve pain and subsequently the providers change the short-acting tablets to long-acting tablets of opioid pain medications. Initially, following this change, patients tend to require only a low dose of these long-acting and more potent medications. Over time, though, the same thing that happened with the short-acting opioids happens with the long-acting opioids. Namely, patients tend to need more of the long-acting opioid medications to achieve the same level of pain reduction. Maybe, at the time, no one seems too concerned because the dose of the long-acting opioid remains low. As time goes by, however, patients come to require greater and greater doses and at some point they are now on moderately high doses of opioids in order to maintain adequate pain relief. Still further in time, even these moderately high doses no longer seem to be enough and patients find themselves needing high doses of the most potent opioid medications in order to obtain the same level of pain reduction that was once achieved with one or two short-acting opioid tablets – back when they first started taking opioids for pain.

Notice that this typical trajectory is not addiction to opioids. People become tolerant to opioids whether or not they ever become addicted to opioids. It is a physiological function of the body’s interaction with the medication and will occur as long as one takes the medication on a regular or daily basis for an extended period of time.

Notice too that patients can become tolerant to opioids even if they never do anything wrong with regard to the use of their medications. They might always take the medication exactly as prescribed, never varying from their prescribed doses, and still patients will become tolerant to the medication. If they take opioids on a consistent basis for a long enough period of time, they become tolerant.

As such, tolerance is a normal phenomenon that occurs when taking opioids over a long-term basis.

Tolerance is a problem

Tolerance to opioid pain medications is a problem if you are not elderly and have a normal life expectancy. When patients with chronic pain begin to take opioid medications for pain, as prescribed by their healthcare provider, at middle age, or younger, they commonly become tolerant to high doses of opioid medications long before they ever become elderly. That is to say, at some point, even high doses of opioids will no longer work to reduce pain and yet patients will have many years yet to live.

The significance of this issue of tolerance is that, for many, if not most, people, opioid pain medications do not work well indefinitely. To be sure, for acute injuries and for post-surgical pain, opioid pain medications seem quite effective at reducing pain. Notice, though, what typically happens in these scenarios: upon healing from the injury or surgery, most people stop taking the medications. In such cases, there is no opportunity to become tolerant because the persons taking them do not remain on opioids for a long enough period of time.

When first starting to take opioid medications for chronic pain, most patients similarly find them quite helpful at reducing pain. Unlike acute injuries or surgery, however, patients with chronic pain do not ever have an occasion to stop taking them – they do not undergo the same process of healing as people do with acute injuries or following surgery. Rather, people with chronic pain continue to have pain indefinitely. So, they typically do not stop taking opioids and so remain taking opioid medications on a long-term basis.

Because of tolerance, though, it is typically not realistic to think that opioids will remain effective indefinitely. Most people require more and more of the medication to achieve the same level of effect. At some point, even high doses of opioids don’t seem to work very well.

If you have many years yet to live, that’s a problem.

The practical limits to opioid dosing

Most healthcare providers acknowledge some upper limit for the safe consumption of opioids. Side effects such as sedation, cognitive dulling, and constipation become too great at high doses. More importantly, accidental overdose can occur with long-term use of high doses of opioids. We are currently witnessing epidemic levels of accidental overdose due to opioid use. For these reasons, most reputable healthcare providers set an upper limit to the amount of opioids when prescribing opioids for a condition, such as chronic pain.

This fact thus points to a difficult conclusion about tolerance to opioids: when patients take opioids for chronic pain for a long enough period of time, they tend to become increasingly tolerant over the years and subsequently reach the upper limits of prescribing. Thus, they become tolerant to even the highest doses of opioids, and yet they may have half their life (or a decade or two) yet to live.

Unintended consequences of long-term opioid use

If patients really knew the long-term consequences of persistent opioid pain medication use, how many would agree to obtain pain relief today at the cost of making the medications no longer effective in the future? The answer remains uncertain, of course, but common sense might suggest that at least some patients, if not many patients, might think twice before consenting to long-term opioid management.

Why? At some point in the future, they may require such medications for an altogether different problem besides chronic pain.

What will they do if they are elderly and fall and break a hip? What will they do if they develop cancer down the road? What will they take for post-surgery pain if they need a surgery at some point later in life?

In cases of terminal illness, like cancer, we don't tend to worry about tolerance to opioids. The sad fact is that people die with terminal illnesses and so if they come to require high doses of opioids it’s okay. They don’t have long to live.

With chronic pain, it's different. Most people with chronic pain will die with chronic pain, not from it. Indeed, they may have a long life ahead of them. As such, they may have an altogether different need for these medications, which is unrelated to their chronic pain, at some time in their future.

When people become tolerant to the highest doses of opioids and subsequently have an altogether different need for such medications besides chronic pain – like cancer, a broken hip, or a surgery, they come to have pain that is very difficult to treat. The highest doses of opioids – the doses that they are already taking – won’t work very well for this new type of pain.

A couple of things can tend to happen in such cases. Healthcare providers think that the high doses of medications the patients are already taking should be sufficient to treat the pain and so don't prescribe anything for the additional pain. Alternatively, healthcare providers place the patient on even higher doses of opioids, which puts the patients at risk of excessive sedation, opioid intoxication, becoming tolerant to even higher than high doses, or, worse yet, accidental overdose.

The rate of accidental overdose to opioid pain medications is, in fact, at an all-time high, at least in the United States.6

Another unintended consequence of tolerance to opioid pain medications is that such tolerance likely remains for a long time even after tapering from the medications. While the findings are not yet definitive, research on methadone maintenance patients (methadone being a type of opioid medication) and animals suggest that, once tolerant to opioids, individuals remain largely tolerant for up to years after cessation of the use of these medications.7, 8, 9, 10 What this might mean is that stopping the use of opioid pain medications for some period of time does not necessarily resolve the problem of tolerance. To be fair, it probably lessens their degree of tolerance, but it does not go away entirely. Once patients become tolerant to opioids they are apt to remain at least somewhat tolerant for the foreseeable future even if they stop using the medications. So, again, the concern remains: what might patients who are presently tolerant to opioids use to control pain in the future if they have an altogether different serious injury or illness or surgery?

Ethics of opioid management in light of the issue of tolerance

All these problems with tolerance to opioid pain medications point to an inevitable conclusion: for many, if not most, people with chronic pain who are not already elderly or have a terminal illness, it is unrealistic to think that the long-term use of opioid pain medications will remain effective indefinitely – for the twenty to thirty to forty years that patients might have yet to live.

As a whole, the field of chronic pain management has done a poor job of acknowledging the long-term consequences of tolerance to opioid medications and discussing it with patients and the public. To be fair, it is somewhat understandable. There is a certain immediacy about being in pain, a need to do something about it now. This immediate need can easily lead to a rationale for providing opioid pain medications today while at the same time tending to overshadow any potential concerns about whether the treatment plan is sustainable, say, ten years from now. Moreover, in years past, it was common for thought leaders and other healthcare providers to declare that, like addiction, tolerance to opioids was rare11, 12 or clinically irrelevant.13 Just like previous assertions about addiction, the field has been forced to re-think these assertions about tolerance and acknowledge that it does occur. We have now had a generation of patients on long-term use of opioid medications for chronic pain and it is commonplace to see patients on high doses of opioids reporting high levels of pain. The explanation is opioid tolerance. Over the years, through no fault of their own, they have become increasingly tolerant and are now tolerant to even the conventionally agreed upon upper limits of doses.

Tolerant patients, for example, are commonly seen in interdisciplinary chronic pain rehabilitation programs – the traditional alternative to long-term opioids for managing chronic pain. They often get referred because they have been on opioid pain medications for ten or fifteen years and are subsequently tolerant to high doses of the medications. Their prescribing provider has become uncomfortable with any further dose increases and yet their present dose is no longer helpful in reducing pain. Fortunately, interdisciplinary chronic pain programs are quite effective relative to other traditional pain management treatments.14, 15, 16, 17 So, help is available.

Nonetheless, it raises the ethical question: Should the field of chronic pain management continue a wide-scale practice of long-term opioid management for chronic pain patients who are neither elderly nor terminal when most of those patients will become tolerant to high doses of opioids long before they ever become elderly or terminal? Should we continue to privilege the present relief of chronic pain over painful acute or terminal conditions of the future? Should this practice continue especially when we currently have an empirically supported, effective alternative to managing chronic pain in the present – the interdisciplinary chronic pain rehabilitation program?

Such programs allow patients to learn how to self-manage chronic pain without the use of opioid medications. In doing so, they resolve the ethical dilemma between treating chronic pain now versus treating painful acute and terminal conditions of the future. By participating in an interdisciplinary chronic pain rehabilitation program, patients can have both: they acquire the abilities to manage their present chronic pain while keeping the effectiveness of opioid medications available to them for treating painful acute or terminal conditions of the future.

It seems reasonable that patients with persistent pain should have this choice before they agree upon a treatment strategy that involves long-term opioid management. For full informed consent to occur with regard to these options, patients would need to understand the long-term, unintended consequences of managing chronic pain with opioids. It would become necessary therefore for the field of chronic pain management to fully and frequently acknowledge these consequences and discuss them with our patients. Such discussions, it seems, have yet to occur on any wide scale basis.


1. Portenoy, R. K., & Foley, K. M. (1986). Chronic use of opioid analgesics in non-malignant pain: Report of 38 cases. Pain, 25(2), 171-186.

2. Porter, J., & Jick, H. (1980). Addiction rare in patients treated with narcotics. New England Journal of Medicine, 302(2), 123.

3. Hojsted, J., & Sjorgen, P. (2007). Addiction to opioids in chronic pain patients: A literature review. European Journal of Pain, 11, 490-518.

4. Martell, B. A., O’Connor, P. G., Kerns, R. D., Becker, W. C., Morales, K. H., Kosten, T. R., Fiellin. D. A. (2007). Systematic review: Opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction. Annals of Internal Medicine, 146, 116-127.

5. Savage, S. R., Joranson, D. E., Covington, E. C., Schnoll, S. H., Heit, H. A., & Gilson, A. M. (2003). Definitions related to the medical use of opioids: Evolution towards universal agreement. Journal of Pain and Symptom Management, 26(1), 655-667.

6. Center for Disease Control and Prevention. (2010). Unintentional drug poisoning in the United States. Retrieved from http://www.cdc.gov/homeandrecreationalsafety/pdf/poison-issue-brief.pdf

7. Thornton, S. R., & Smith, F. L. (1998). Long-term alterations in opiate antinoception resulting from infant fentanyl tolerance and dependence. European Journal of Pharmacology, 363(2-3), 113-119.

8. Chiang, Y., Hung, T., Lee, C., Yan, J., & Ho, I. (2010). Enhancement of tolerance development to morphine in rats prenatally exposed to morphine, methadone, and buprenorphine. Journal of Biomedical Science, 17, 46.

9. Lim, G., Wang, S., Zeng, Q., Sung, B., & Mao, J. (2005). Evidence for a long-term influence on morphine tolerance after previous exposure: Role of neuronal glucoticoid receptors. Pain, 114, 81-92.

10. Mao, J., Sung, B., Ji, R., & Lim, G. (2002). Neuronal apoptosis associated with morphine tolerance: Evidence for an opioid-induced neurotoxic mechanism. Journal of Neuroscience, 22, 7650-7661.

11. Heit, H. A. (2001). The truth about pain management: The difference between a pain patient and an addicted patient. European Journal of Pain, 5 (suppl. A), 27-29.

12. Portenoy, R. K. (1996). Opioid therapy for chronic nonmalignant pain: A review of the critical issues. Journal of Pain and Symptom Management, 11(4), 203-217.

13. Collett, B. J. (1998). Opioid tolerance: The clinical perspective. British Journal of Anaesthesia, 81, 58-68.

14. Flor, H., Fydrich, T., & Turk, D. C. (1992). Efficacy of multidisciplinary pain treatment centers: A meta-analytic review. Pain, 49(2), 221-230.

15. Gatchel, R., J., & Okifuji, A. (2006). Evidence-based scientific data documenting the treatment and cost-effectiveness of comprehensive pain programs for chronic non-malignant pain. Journal of Pain, 7, 779-793.

16. Guzman, J., Esmail, R., Karjalainen, K., Malmivaara, A., Irvin, E., & Bombardier, C. (2001). Multidisciplinary rehabilitation for chronic low back pain: A systematic review. BMJ, 322(7301), 1511-1516.

17. Turk, D. C. (2002). Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. The Clinical Journal of Pain, 18, 355-365.

Date of publication: July 10, 2014

Date of last modification: September 8, 2016

Murray J. McAllister, PsyD, is a pain psychologist and consults to health systems on improving pain. He is the editor and founder of the Institute for Chronic Pain (ICP). The ICP is an educational and public policy think tank. In its mission is to lead the field in making pain management more empirically supported, the ICP provides academic quality information on chronic pain that is approachable to patients and their families. 

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