Opioid Tolerance or Hyperalgesia? Key Symptoms Offer Clues

Nancy A. Melville

September 16, 2013

LAS VEGAS — Patients with chronic pain being treated with opioids can commonly be expected to develop tolerances to the drug with longer-term treatment, but the emergence of certain, uniquely sensitive pain characteristics can be red flags for a potential differential diagnosis of hyperalgesia, said pain specialist Sanford M. Silverman, MD.

Concerns about hyperalgesia as opioid overuse in general faces intense public and regulatory scrutiny were evident from the overflowing crowd spilling out into a hallway at the meeting to hear Dr. Silverman address the issue here at PAINWeek 2013.

"Hyperalgesia is not easy to diagnose," said Dr. Silverman, who is medical director of Comprehensive Pain Medicine in Pompano Beach, Florida.

"When a chronic pain patient isn't getting better, a clinician asks: is the patient developing a tolerance and needs more opioid or does he have opioid-induced hyperalgesia?"

Key Symptoms

Key symptoms offer important clues, Dr. Silverman said. Patients with opioid-induced hyperalgesia will develop an increased sensitization to pain that may be unlike their original pain.

"The first thing to understand is this is a diffuse, spreading kind of pain," he said. "Patients develop an acute insensitivity to pain even though they may be stable and functioning on their opiates."

The distinction from the development of a tolerance should be clear. "This is not just a lack of efficacy of the pain medicine — that's tolerance, and everybody develops a tolerance to almost every exogenous thing. It's a defense mechanism your body engages in and is not hyperalgesia."

A classic case of hyperalgesia will be a patient who initially presented with postlaminectomy syndrome with back and leg pain and has been receiving opioid therapy for years.

"Now you start noticing something different — the patient's pain diagram is spreading, and now he also has headaches, neck pain, arm pain."

"That's opioid-induced hyperalgesia," Dr. Silverman said. "Not only is the back and leg pain worse, but now the fire has spread and kind of gone out of control."

A stabilizing of symptoms when opioids are increased should be a tip-off that the patient has in fact developed a tolerance to the drugs, and the response should help to disprove a diagnosis of hyperalgesia.

Conversely, with hyperalgesia, there may also be an initial response, but the relief is typically fleeting.

"If an increase in opiates results in only temporary relief or a worsening of symptoms, that's opioid-induced hyperalgesia," Dr. Silverman said. "They will get better for a while, but then they only get worse. Their normal pain will not only increase, but it will spread and become multimodal."

Importantly, clinicians should rule out other factors, including the progression of a disease, such as cancer, or a new injury causing new pain.

Additionally, hyperalgesia should not be mistaken for allodynia. Whereas hyperalgesia is characterized as a painful response to painful stimuli, allodynia involves oversensitized, increased pain in response to even nonpainful stimuli, such as just brushing against the skin.

"Zoster (shingles) is a good example of allodynia," Dr. Silverman explained.

Opioid-Induced Hyperalgesia Treatment

When clinicians have ruled out an opioid tolerance and suspect opioid-induced hyperalgesia, an initial strategy should be to reduce the opioid dose. One important approach is to use rational polypharmacy, "using a medicine to treat with one mechanism and another medicine to treat another mechanism," Dr. Silverman recommended.

Opioid-sparing adjunct treatments can be important, as can interventional techniques. "Sometimes just a simple thing like an injection into a muscle or a nerve block can help as well," Dr. Silverman said.

Opioid rotation or medically supervised withdrawal can be a useful strategy; however, caution should be used when switching a patient to methadone.

"There are reports of people becoming hyperalgesic on methadone as well," Dr. Silverman cautioned.

"In addition, you need to be very careful in converting patients due to incomplete cross-tolerance. The dose conversion isn't linear — the conversion ratio is very tricky and my advice would be to go low and slow because this is how patients can get into trouble and even die. Use this with caution."

[T]he conversion ratio is very tricky and my advice would be to go low and slow… Dr. Sanford M. Silverman

Dr. Silverman said he has also had some success with buprenorphine but warned that, while it has been shown to enhance the ability to treat opioid-induced hyperalgesia, some patients experience withdrawal when switching to the drug.

Importantly, clinicians should make sure to keep opioid-induced hyperalgesia on their radar when prescribing the drugs — particularly for patients receiving high doses.

"Be aware of opioid-induced hyperalgesia," Dr. Silverman recommended. "It's not going to be the first thing on your mind, but keep it in the back of the mind."

In addition, "Have an exit strategy when you use opioids in general because you could develop these problems and you will need to back out."

Pain Quality

Commenting on the issue of opioid-induced hyperalgesia in general, pharmacologist James B. Ray, PharmD, CPE, expressed skepticism on whether the condition is as prevalent as some clinicians believe.

"I have seen clinicians call a problem opioid-induced hyperalgesia when the characteristics of spreading pain and changes in the characteristics of the pain quality like the development of allodynia becomes present," said Dr. Ray, who is the clinical pharmacy coordinator for pain and palliative care at the University of Virginia Health Center in Charlottesville.

"[Furthermore], any significant increase in dosage without substantial improvement in pain seems to get labeled as opioid-induced hyperalgesia," he told Medscape Medical News.

"Some surgeons are using this as justification for tapering patients off of opioids prior to surgery, so that 'the opioids will work, otherwise your postoperative pain will not be able to be controlled'," he said.

Actions wind up being taken despite confusion about the issue, he warned.

"There is a tremendous amount that we still don't understand about opioid-induced hyperalgesia and I think it may not be as prevalent as we believe; I have seen cases but certainly not on a daily basis."

Dr. Silverman has disclosed no relevant financial relationships. Dr. Ray is a consultant and on the speaker's bureau for Millennium Laboratories and a consultant to Cadence Pharmaceuticals.

PAINWeek 2013. Presented September 6, 2013.


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