Friday, January 13, 2012

Could High-Dose Opioids Conquer Chronic Pain?

Brief Note Contrary to concerns professed lately by opponents of opioid analgesia, higher than usual doses of these medications could be just the thing to prevent acute pain from becoming a chronic, life-changing malady. As was recently successfully demonstrated in a preclinical study, the concept of early, short-term, high-dose opioid administration to quickly manage pain is a radical departure from usual practice and may offer interesting possibilities for better pain care.

In the study — published recently in the journal Science [Drdla-Schutting et al. 2012], and further reported in the journal Nature [Frood 2012] — researchers at the Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, report discovering new effects of opioids when given at a very high dose rather than continuously at typical lower does.

According to the articles, chronic pain in many cases is a nerve condition lingering long after an acute pain-causing stimulus has receded. One of the researchers, Jürgen Sandkühler, notes that acute stimuli can change how the central nervous system deals with pain. In a model known as long-term potentiation (LTP), nerves carrying pain signals may fire repeatedly, turning on a cellular pain amplifier that influences the development of a chronic pain state. Opioid analgesics at usual doses can be effective, at least short term, but they often have limitations in some patients for providing ongoing relief of chronic pain.

Sandkühler and colleagues decided to push the boundaries of opioid actions to see whether the drugs could impact the underlying LTP problem of chronic pain at an early stage. The team induced LTP in 25 rats by exposing nerve fibers known to carry pain signals to either low- or high-frequency electrical stimulation, and some of the animals were injected with capsaicin, the pain-causing ingredient in chilli peppers, as an alternative noxious stimuli. Essentially, the three types of stimuli induced acute pain and then chronic hyperalgesia in the animals.

After the pain stimulus was discontinued, the researchers gave the animals very high intravenous doses of remifentanil, a potent ultra-short-acting opioid often used as a component of surgical anesthesia. As expected, the acute-pain signaling declined immediately upon opioid administration; however, once the short-term opioid effects wore off, the hyperalgesic chronic pain effects of LTP also were significantly reduced. A second infusion of remifentanil an hour later abolished LTP completely and restored the animals' pain sensitivity to normal. Similar beneficial effects were found in rats treated with all 3 forms of pain-inducing stimulation.

The high-dose opioid not only dampened acute pain but erased memory traces of pain in the central nervous system. However, treating the animals with only half the dose of remifentanil did not produce the same benefits. Sandkühler suggests that a threshold level of the drug is needed to disrupt the movement of calcium signalling ions between nerves and thereby neutralize the LTP.

“The dose of drugs we use is very high, probably 2 to 4 times higher than used for normal pain control,” Sandkühler states in the Nature article. “The animals almost stop breathing, which is probably one reason why this was not discovered before.” But he adds that the equivalent high dose amount of the opioid for a human is well below a fatal dose, and some early experiments have shown that people can tolerate it.

COMMENTARY: Normally, we do not report on preclinical experiments in animals for the obvious reason that whatever is found may have no clinical validity in humans. This also could be the case here; however, this research is rather provocative in that the scientific rationale appears to have some merit, yet the approach contradicts current attitudes and practices regarding opioid therapy.

There has been some discussion in the literature that, by treating acute pain of various types quickly and aggressively, the chances of it becoming a chronic condition might be reduced. However, opioids are often avoided if possible as acute-pain therapy, and the current advice of “start low and go slow” when it comes to opioid dosing might actually favor in certain cases the development of long-term potentiation (LTP) that fosters chronic pain. Perhaps, what is most needed is higher rather than lower opioid dosing at the outset, at least for a brief period of time and, certainly, under safe conditions.

Of course, much more research is needed to assess the opioid agents, doses, patients, and acute pain conditions that are most amenable to this approach; and, its safety. Meanwhile, it is merely something to think about.

REFERENCES:
> Drdla-Schutting R, Benrath J, Wunderbaldinger G, Sandkühler J. Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration. Science. 2012(Jan 13): 235-238 [
abstract here].
> Frood A. High-dose opiates could crack chronic pain; powerful analgesics can restore normal nerve function. Nature. 2012(Jan 12) [
article available here].

4 comments:

Robert Root said...

The consequences of a "cellular pain amplifier" never being stimulated is one I'm familiar with. After awakening from a full knee replacement surgery the orthopedist started "very low and stayed there." For three days I writhed in pain that can't be described save to say during several half-hour sessions of mechanically induced movement. I felt tightening in my chest as if a band was being tightened. After days and weeks of rehab, I developed an infection in the new knee and it had to be removed. By that time, I had decided that I would not put myself through another torturous surgery. Prior to my surgery I ask to speak with the anesthesiologist, and I requested that he do a nerve block such that my leg from the waste down was without feeling. Upon awakening post-op, I had no feeling in my leg and the block remained in for 36 hours. The pain from that surgery never materialized, and I was far the better for it. They reinstalled the knee one year later, and again I requested and received a nerve block and I never did experience a fraction of the pain I had after the first surgery.

I have hence had surgery on my elbow with a block and again no pain. So I was looking for words to describe the fact that the pain channels never opened up and I never felt enough pain to warrant pain medication. This dramatic difference needs further study. I know my anesthesiologist now offers the block for surgeries on the extremities, and my cardiologist found that 10% of my heart is now dead by what he calls a "silent heart attack." I believe I know just when that occurred, and with a open minded anesthesiologist it will never happen again. I believe that if the "cellular pain amplifier" never gets started, thus the activation threshold is not approached, then the perceived pain is exponentially reduced. I will never go through another surgery on the extremities without a nerve block. --- RR

FRANK CARMEN, L.r.c. said...

This is my response to the Article,
"Could High-Dose Opioids Conquer Chronic Pain?"

My response has to be VERY short, because I have to leave {in 5 minutes} to go to a Conference {on Pain} at which I am speaking.

While the Compassionless Field of "modern" (sic) Medical Research {which includes MOST Physicians} researches "High Dose Opioids/Opiates" for pain at the pace of a snail, I have actually been in a real "High Dose Opioids for Intractable Pain" Clinic/Program, Legally & Ethically taking at least 96 mg. of Hydromorphone {"Dilaudid"} daily AND 30 mg. of Levorphanol daily {or 120 mg. Oxymorphone ("Opana") }, for 272 consecutive Months! I started in May 1989. And since the cause of my Intractable Thoracic Back pain & my Right-Shoulder & Arm pain {RSD} has no Cure, I stay on my daily Opioids regime to this day! There are another 125 of us in the Program I am in. I have been in it the longest. I have suffered ZERO negative effects during this time, I drive every day with ZERO impairment, and I have NEVER ONE TIME experienced Opioid-induced Euphoria {meaning I have NEVER gotten High-- not even for one Minute}!

I have written in length, here at this Website, many times in the Past about my case & experiences.

Without these High DAILY Doses of Opioids, I would have no life! Without the daily Opioids, I can not use my right Arm & Hand, and my Back Pain would make me sit in a recliner-chair all day & night!

YES-- High Dose Opioids IS a SAFE option for severe, 24/7/365 #8 to #10 Pain! Under strict supervision by a Pain M.D. with Monthly Appointments & Testing or Examinations, this level of Opioids intake is Both safe and Legal! And a Life Saver!

I'll write a longer Post in a few days.

Anonymous said...

I too must take high does opoids to control severe back and leg pain. I meet every 6 wks with my doctor and credit him with saving my life. If I had not found this wonderful physician my life would be a living hell. I have never once gotten a high from any dosage I have taken. We started low and titrated up to a dose that would control my pain. I work every day and even though my pain is never a zero it is controlled. I appreciate all the education you do concerning pain management. Thank You

nick said...

i to take 400mg of Morphine Sulfate ER per day with Opana IR 10mg tabs 2per dose 4 times per day 80mg total, and 5 Hydromorphone 8mg tabs for brkth. pain and i just now got a little control. i follow all the rules so my doc trust me which is essential. i have found if your take certain supplements your opioid meds would last life-long. Amino-acid comples, taurine, L-Glutamine, Alpha-Lipoic Acid, Foloc acid,5-HTP,DL-Phenylalanine, L-Arginine, and Calcium/Magnesium/vit. d/phosphurus or Boron 3mgs or less. and a good multi-vit and min for men or whomen and the meds have the raw materials to work the best