Is Opioid Induced Hyperalgesia a Clinical Reality?

Most “studies” and “research” and pure rantings involving chronic opioids for chronic pain mention that pain patients on high opioid doses might have (must have) hyperalgesia, meaning the opioids themselves are causing the pain. They make it sound like a known scientific fact that that OIH causes problems for many patients who take opioids. but this has *never been proven* in humans.

If you’ve been told by anyone that your pain must be hyperalgesia, you can point them to this article, which summarizes the current evidence and presents a survey that only proves that some doctors suspect it sometimes.

JPM | Free Full-Text | Opioid Induced Hyperalgesia, a Research Phenomenon or a Clinical Reality? Results of a Canadian Survey | HTML – April 2020  


Very little is known regarding the prevalence of opioid induced hyperalgesia (OIH) in day to day medical practice.

The aim of this study was to

  1. evaluate the physician’s perception of the prevalence of OIH within their practice, and
  2. to assess the level of physician’s knowledge with respect to the identification and treatment of this problem.


An electronic questionnaire was distributed to physicians who work in anesthesiology, chronic pain, and/or palliative care in Canada.


Of the 462 responses received, most were from male (69%) anesthesiologists (89.6%), in the age range of 36 to 64 years old (79.8%).

In this study, the suspected prevalence of OIH using the average number of patients treated per year with opioids was 0.002% per patient per physician practice year for acute pain, and 0.01% per patient per physician practice year for chronic pain.

Most physicians (70.2%) did not use clinical tests to help make a diagnosis of OIH.

So, they are essentially just guessing.

The treatment modalities most frequently used were

  • the addition of an NMDA antagonist,
  • combined with lowering the opioid doses and
  • using opioid rotation.


The perceived prevalence of OIH in clinical practice is a relatively rare phenomenon.

And this just speaks to the “perceived” prevalence without making any claims about the “real” prevalence.

Furthermore, more than half of physicians did not use a clinical test to confirm the diagnosis of OIH.

The two main treatment modalities used were NMDA antagonists and opioid rotation.

The criteria for the diagnosis of OIH still need to be accurately defined.

The above was only the abstract – annotations from the free full-text are below:


The purpose of this study was to evaluate physicians’ perceptions of the prevalence of opioid induced hyperalgesia within their practices.

Additionally, the authors wished to propose a guide for the diagnosis and treatment OIH using the clinical experience of doctors who work in pain management.

This study hopes to provide clinical data that will help outline the magnitude of this problem within current practice.


Opioid induced hyperalgesia (OIH):

The definition of OIH that the authors used is that reported in Pain Physician 2011. It reads as follows:

“State of nociceptive sensitization caused by exposure to opioids.”

The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain becomes more sensitive to certain painful stimuli.

When they cannot even state with confidence that a pain is actually nociceptive (not inflammatory or from central sensitization), how can they assume to know that it’s from hyperalgesia when they can’t test to see if it would be any different without the opioid?

The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. This phenomenon can occur at very small doses of opioids (at the beginning of treatment) but most often is seen with analgesic doses”.

Opioid tolerance (OT):

Tolerance is a pharmacologic concept that occurs when there is a progressive lack of response to a drug, thus requiring increasing dosing, which can occur with a variety of drugs, not limited to opioids. An increase in the dose of opioids will improve analgesia

Withdrawal-associated hyperalgesia (WAH): WAH is the experience of diffuse joint pain and body aches, which occur when detoxifying from opioid use or skipping/missing scheduled doses; it is time-limited and can be treated with Non-steroidal Anti-inflammatory Drugs (NSAIDs), clonidine, a controlled taper of an opioid (if desired), or a strict schedule of opioid dosing

Chronic pain (CP):

Chronic pain is defined as persistent or recurrent pain lasting longer than three months. This definition, which incorporates the duration of pain, has the advantage being clear and operationalized

Chronic pain can be subdivided into chronic primary pain, chronic cancer pain, chronic postsurgical and post traumatic pain, chronic neuropathic pain, chronic headache and orofacial pain, chronic visceral pain, and chronic musculoskeletal pain. Chronic primary pain is pain in one or more anatomic regions that persists or recurs for longer than three months, and is associated with significant emotional distress or significant functional disability.


Table 1. Number of patients in whom physicians suspected opioid induced hyperalgesia (OIH) in an acute and chronic pain setting by physicians over their total career at the moment of survey (n = 302).

Using the calculations presented above, the prevalence estimate for OIH is 7.9 cases per practice year in the acute pain setting and 6.8 cases of OIH per practice year in the chronic pain setting.

The 416 physicians who responded to the questionnaire treated an

  • average of 7330 patients with opioids per week.
  • Using 46 weeks a year, it is estimated that they saw over 337,180 patients a year.

As they had suspected an average of 7.9 cases per practice year in the acute pain setting, this is a risk of 0.002% per patient per physician practice year (Table 5).

The results of this study suggest that OIH may not be as prevalent in the clinical setting as was once thought.

The responses revealed a significant knowledge gap in 27% of responders (198) regarding the differential diagnosis and management of OT and OIH.

Although there are several publications supporting the hypothesis of OIH, especially in acute post-operative pain, there are also published studies that do not support the hypothesis.

For example, of 3 experimental studies evaluating OIH in healthy subjects two showed positive results for OIH while one showed negative results.

Despite the existence of several articles that discuss the prevalence of OIH in animals, as well as in patients with acute, chronic and oncological pain, there are none that speak about the prevalence of OIH in clinical practice.

Here’s the proof we need to show that OIH is highly unlikely to be a factor in our pain and we cannot allow doctors to make such an assumption.

Although 63% of the study sample stated that they had suspected OIH at least once during their career at least half of the respondents had been in practice for over 15 years, making the overall frequency extremely low.

Additionally, physicians did not report a high suspicion OIH in the chronic pain population.

Since the suspicion of OIH is low in physician specialists it is likely that the probability of OIH diagnosis by a general physician is much lower.

Despite the fact that patients with chronic non-cancer pain receive high doses of opioids reports of OIH in the chronic non-cancer pain population are rare.

OIH seems to be even less prevalent in cancer pain.

Adding to the difficulties in diagnosing OIH are a lack of understanding and systematic application of the definitions for OIH, opioid tolerance (OT), and withdrawal associated hyperalgesia (WAH).

A systematic review including 1494 patients from 27 randomized-control clinical trials showed that patients treated with high doses of remifentanil during surgery had a small, but statistically significant, increase in acute post-operative pain compared with the reference group. In almost all of the reported instances of OIH, the diagnosis was made after the cessation of an opioid infusion. Other authors show similar results with remifentanil. This begs the question of what was really being measured? Was it OIH, OT, or WAH?

Although OIH has been cited as a potential cause of opioid dose-escalation without resultant analgesia, veritable proof of that notion is relatively limited. Most of the studies proposing this are either in vitro or on animals, in the post-operative acute pain setting, or in healthy volunteers. Only a few studies have discussed chronic non-cancer pain and palliative care. In such cases, it is difficult to sort out whether or not this was OIH or whether it may in fact have been OT or WAH.

The human data are far from clear or being related to the challenges in defining, identifying, diagnosing, and treating OIH. The present study demonstrates that ensuring the correct diagnosis and treatment of OIH requires an improvement in physicians’ knowledge related to OIH, as well as the performance of an adequate physical examination.

Indeed, doctors don’t know enough about OIH to be making so many statements about it.

Although there are similarities in the clinical manifestations of OIH, OT, and WAH, treatment for each of these entities is quite different.

As this study underlines, a clear differentiation of OIH from OT and WAH is essential in order to provide appropriate and targeted treatment.

As a step toward this goal, the authors provide an algorithm for clinicians faced with a suspected case of OIH that is both consistent with the evidence from this study, and that incorporates directives from the current literature. The suggested algorithm (Algorithm 1) follows three basic steps, namely:

(1) in the presence of suspected OIH, look for specific symptoms and exclude the possibility OT and WAH;

(2) use clinical tests to make the diagnosis;

(3) and treat OIH using a stepwise approach with various proven effective options

(Figure 1).


This study confirmed that OIH was not as prevalent as had been anticipated, and that the clinical prevalence of OIH in patients after surgery, as well as those suffering from chronic non-cancer pain or chronic cancer pain, is unclear.

Additionally, almost 3/4 of physicians did not use a clinical test to ascertain a diagnosis of OIH, which may cause confusion in the clinical interpretation and management of the condition.

I’ve posted several articles like this that discuss hyperalgesia, or rather, the lack thereof:

Yet doctors continue “believing in” it and using it to deny pain relief:

Other thoughts?

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.