The Truth About Hyperalgesia

Demystifying Opioid-Induced Hyperalgesia – By Jennifer P. Schneider, MD, PhD – Feb 2019

Some insurance companies have declined to continue paying for opioid medications, citing OIH. Here’s why.

In cases like these, many insurance companies state that patients should have their doses tapered in order to decrease their pain.

Now, we’re really living in a fun-house mirror world, where taking a pain reliever increases pain and taking away opioid pain relief decreases it.

However, clinicians may find that attempts to reduce the opioid dose often result in increased pain.

Ya think? 

Hyperalgesia refers to an exaggerated pain response.

Opioid-induced hyperalgesia (OIH) has been suggested as an explanation for the decreased analgesic efficacy of opioids in some patients treated chronically with high opioid doses.

Studies have shown some evidence of OIH in rats.One study reported a receptor in the genome of rats and mice which may play a role in producing OIH in these animals.

We are learning in many areas of the life sciences that results in rats do not always translate well into results in humans. (Perhaps this is because most people are not rats.)

Several studies in humans showed that patients who received acute intraoperative intravenous remifentanil, an opioid related to fentanyl, experienced increased post-operative pain in the recovery room, as determined by pain scores, morphine requirement, and/or sensory testing.

Such studies have been interpreted to show that acute opioid administration rapidly produces hyperalgesia.

This setting is different, however, from those where patients who have chronic pain and are treated with chronic opioids gradually require increasing doses.

Evidence from the Literature

An observational study compared the pain sensitivity in three groups of patients:

• those with non-cancer chronic pain;
• patients without chronic pain who were maintained on methadone for addiction therapy; and
• a control group.

The first two groups had increased pain sensitivity to one stimulus (cold pressor test) but not another (electrical stimulation), and none of the groups exhibited allodynia.

The results suggested that chronic opioid use may increase sensitivity to specific pain stimuli but not others, and does not produce allodynia.

Despite these experimental studies, no published studies have

• either specifically evaluated the relevance of OIH to clinical populations of chronic pain patients
• or provided evidence that OIH actually contributes to increased opioid need in chronic pain patients.

Even though these studies don’t exist, most people assume they do. You can point to this article to set them straight.

One long-term outcome study followed 197 patients who were on chronic opioids for at least 1 year; the mean duration of opioid treatment was 56.5 months and the mean daily dose was 180 mg morphine equivalents.

Patients who required dose increases with time usually had disease progression.

This is always ignored when milligrams of opioids are studied. Researchers always assume that an increased dose is due to tolerance or even abuse or addiction, yet such increases in both pain and opioid dose are to be expected as a person ages.

The authors wrote: “The patients showed no apparent evidence of tolerance or hyperalgesia, despite being on what are considered moderate to high opioid doses…These results demonstrate that a significant proportion of opioid-treated chronic pain patients can remain on the same dose of opioid for years.”

I wonder how many pain patients have tried to tell their medical providers this and have only been ignored or even rebuked, and told the “common knowledge” that

“if you take opioids (at any dose, for any reason),

you will become tolerant and

you will need higher and higher doses forever.”

This is another case of “common knowledge” being only “common foolishness” and “common gullibility”. The tolerance developed is to their euphoric effect, like when injecting opioids for the “high”, not to their pain-relieving effects.

From the Experts

The clinical relevance of opioid-induced hyperalgesia in the setting of opioid therapy for chronic pain has never been shown.

And it’s not just one or two doctors who doubt its existence:

Below are the opinions of several pain experts.

• Fishbain, in an evidence-based structured review, concluded: “There is not sufficient evidence to support or refute the existence of OIH in humans except in normal volunteers receiving opioid infusions.”8
• The conclusion of Reznikov, et al, was: “The clinical relevance of OIH in patients on chronic opioids for pain has never been demonstrated…Administration of commonly used doses of oral opioids does not result in abnormal pain sensitivity beyond that of patients receiving non-opioid analgesia.”
• Regarding OIH, Pasternak was quoted as saying: “There is little question that it exists. The animal models can reliably detect it and, if you look closely enough, you might be able to detect it in human subjects. However, in the clinical setting it rarely, if ever, has a sufficiently robust effect to become a significant issue…”
• When asked how one may avoid OIH, Chou responded: “Data to estimate the prevalence and clinical impact of hyperalgesia in humans, or how to avoid it, are quite limited.”
• Argoff’s answer: “There are truly no good data to support or refute this entity. The quality of currently available studies regarding this matter is generally poor.”11

What Explains OIH?

Depending on the timing, there are three potential reasons other than OIH:

• When an opioid is initially prescribed, the dose is deliberately low in order to assess side effects and then increased to an effective analgesic dose
• A short time after reaching an initially effective dose, the most common reason for decreased pain relief is increased activity, a desirable outcome often requiring a dose increase.
• Decreased efficacy months after a stable effective dose is often due to disease progression.

In other words, there are several well-established reasons other than possible OIH to explain why prescribers often find it necessary to increase the opioid dose in a patient with chronic pain.

If a patient is functioning with adequate pain relief on his/her current dose of opioid, decreasing the dose, as the insurance company may suggest, is not in the patient’s best interest. The outcome of such a decision is likely to be increased pain and decreased function.