Opioid Induced Hyperalgesia Prevented by Buprenorphine?

“Buprenorphine is a kappa receptor antagonist. For these reasons, buprenorphine might be unique in its ability to treat chronic pain and possibly OIH.”

The opioid crisis has been fueled by the use of opioids to treat chronic pain.  Practice patterns have changed, but doctors are still criticized for their roles in the overuse of opioids.  I’ve sat through community ‘heroin forums’ (sometimes on stage) as sheriffs, politicians, and ‘recovered addicts’ firmly pointed fingers at health professionals.  I, meanwhile, kept my finger under the table, but had the thought that some of the people pointing would be the first to complain if they were forced to stop pain medication prematurely for their own good or ‘for the good of the community.’

Doctors can’t see into the future.  I suspect most cases of opioid overuse began with well-intended efforts to provide temporary pain relief.   But then for a variety of reasons things didn’t go as planned.  Maybe the planned knee or back surgery never took place because of patient indecision or insurance problems.  Maybe the lumbar strain didn’t heal after 6-8 weeks the way it was supposed to.  In any case, doctors who work with pain patients know what happens next.  Before the next appointment, the doctor plans to tell the patient that the time has come to stop opioids.  But after that suggestion, the patient replies that the pain is even worse now than when the pain meds were started.  “Actually (says the patient) I was going to ask you to increase the pain medication!”

Some doctors hold fast to their plan and initiate a taper.  Some doctors argue over the issue, and some manage to create enough fear in the office that no patient would dare talk back. Too often, patients are suddenly cut off high doses of opioids, precipitating withdrawal symptoms that drive them toward illicit pills or heroin.  Patients who manage to maintain scripts for opioids embark on a miserable journey that often ends badly.

I’ve converted many pain pill patients to buprenorphine patients over the years.  I could save time using a rubber stamp to document their histories:  (blank)-year-old man was started on pain pills after (blank) injury (blank) years ago; dose was increased over time using oxycodone then OxyContin then fentanyl patches; patient lost the ability to control the medications and ran out early, resulting in discharge from treatment.  Patient presents asking for treatment with buprenorphine.

Many past patients fit this description, riding the gray area between opioid dependence and pain.  Lawmakers and policy-writers seem to believe that most patients are either addicts or pain patients.  Doctors who work in the field know that most patients sit in the middle, with smaller groups on each side. **

I’ve been surprised at how well those pain patients do after changing to buprenorphine.  They usually feel much better overall, which is no surprise given the misery of living according to a cycle of relief and withdrawal.  More surprising is that their pain is reduced, sometimes completely.  I assume the reduction in pain relates to stopping the cycle of relief and withdrawal, although I don’t know the mechanism beyond that idea.  People who take opioids become more ‘somatic’ over time, more and more focused on symptoms including those that warn of impending withdrawal; perhaps buprenorphine reduces that tendency toward somatization.

Which brings us to opioid-induced hyperalgesia or ‘OIH’, where prolonged use of opioids makes pain symptoms worse.  I’m reluctant to go ‘all in’ on OIH, just as I reserved full judgement of the full range of symptoms blamed on TMJ, EBV, IBS, CFS, FM, MCS, WPW, PMS, PMDD, RSD, CRPS, RLS, GAD, SAD, DID, IED, and other ‘initialed diseases’ that have garnered headlines over the years.   (Can you name them all? *** Try THESE )   Attention on OIH has waxed and waned over the years, and is gaining attention now as PROP, the CDC, and SAMHSA talk down opioid use.

LOL.

But seriously, my problem with OIH starts with awareness that pain sensation is very complicated.  Different people describe varying pain intensity for the exact same stimulus.  And even within one patient, intensity varies according to mood, fear, the duration of the pain (expected and actual), the perceived reason for the pain, the perceived harm from the stimulus, the setting (e.g. home vs. laboratory), and many other variables.  It is one thing to see how long it takes a rat to flick its tail when placed over a heat lamp, but another when a human fills out a pain scale.

I also take note of selection bias, a phenomenon that occurs whenever science bumps into political forces where studies citing the occurrence of a phenomenon are more likely to get government funding and editor approval than studies denying the phenomenon.  And no, I’m not a denier—of anything.  But I know bias when I see it. I’ve seen articles that conclude ‘there is not enough evidence to rule OUT the existence of OIH’, which is the opposite of how good science is supposed to be conducted.

You’ll find a great review of OIH here: http://www.painphysicianjournal.com/current/pdf?article=MTQ0Ng%3D%3D&journal=60

A cautious reader of the literature will note that at best, OIH is more of a ‘basic science’ phenomenon than a ‘clinical phenomenon.’   Increased pain sensitivity in response to opioids is subtle.  If it wasn’t, it would have been described decades, even centuries ago.  The linked material references older comments that the authors suggest came from observations of OIH, but to my reading the comments more likely referred to the withdrawal that follows opioid use.  You’ll also notice, if you read the linked article, that most of the studies of OIH in humans look at pain sensitivity in long-term methadone patients.  But you’ll also read that in theory, methadone is one of the least-likely opioids to cause OIH.

Interestingly, the other opioid agent with lower likelihood to cause OIH is… buprenorphine.  From the link above:  Buprenorphine has been shown to be intermediate in its ability to induce pain sensitivity in patients maintained on methadone and control patients not taking opioids. Buprenorphine showed an enhanced ability to treat hyperalgesia experimentally induced in volunteers compared to fentanyl. And spinal dynorphin, a known kappa receptor agonist, increases during opioid administration, thus contributing to OIH. Buprenorphine is a kappa receptor antagonist. For these reasons, buprenorphine might be unique in its ability to treat chronic pain and possibly OIH.

In short, long term use of opioids appears to increase pain sensitivity.  But we are a long way from understanding the extent of that phenomenon.  Some studies suggest that all opioids are not equal in regard to OIH, and I wonder if the reported decrease in pain from relatively minor injuries such as lumbar strain, when people change from opioid agonists to buprenorphine, is caused by a decrease in opioid-induced hyperalgesia.

But then again, maybe those patients just thought they had pain because of a subconscious (or conscious) desire to get pain pills.

For whatever reason, people with chronic pain seem to do well on buprenorphine.  Hopefully all of the concerns over opioids will leave us at least that one treatment option.  Give the extreme safety of buprenorphine, that should be a no-brainer!

**At least that was the case until several years ago, when I began seeing more and more patients who ‘started heroin recreationally’- an oxymoron if there ever was one.

***TMJ = temporomandibular join disorder, blamed for chronic headaches and other symptoms; EBV = Epstein Barr Virus; IBS = irritable bowel syndrome; CFS = chronic fatigue syndrome; FM = fibromyalgia; MCS = multiple chemical sensitivity; WPW = Wolf Parkinson White; PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; RSD = reflex sympathetic dystrophy;  CRPS = complex regional pain syndrome; RLS = restless leg syndrome; GAD = generalized anxiety disorder; SAD = seasonal affective disorder; DID = dissociative identity disorder; IED = intermittent explosive disorder.

8 thoughts on “Opioid Induced Hyperalgesia Prevented by Buprenorphine?

  1. Hi Dr. Junig Thank You for your thoughtful comments.
    The Comprehensive Review of Opiate Induced Hyperalgesia article that you reference above is excellent.

    I think some of the confusion about Opiate Induced Hyperalgesia is that there are two clinical phenomena; Classic OIH, and Rebound Pain.
    Classic OIH is when the pain actually worsens with the administration of an opiate to some susceptible individuals or to some patients receiving high dose opiates and this is not common..
    Rebound Pain is quite common and affects most patients receiving chronic opioid therapy, and is a lesser form of OIH.

    Averaged across a large group opiates reduce pain by about 1/3 (some people get more and some less or no relief).
    However, Tylenol and Ibuprofen reduce pain across the same population by about half.

    I have observed that opiates are most effective at treating the rebound pain that is caused by opiate use. This rebound pain is an expected part of chronic opiate therapy for pain (and seems to occur to a lesser degree with buprenorphine).

    Rebound pain is one of the drivers for continued opiate use and creates the illusion that opiate is relieving the pain when it is actually causing most of the pain it seems to relieve.

    There seems to be a link between rebound pain and the development of post opiate use dysphoria.

    The cartoon model that I share with patients is as follows:

    Opiates imitate endorphins.
    Endorphins are a stress response modulator that dampens the effects of adrenaline and boosts the release of dopamine.
    With Opiate administration:
    If the adrenaline dampening effect predominates the person gets sleepy.
    If the dopamine releasing effect predominates the person feels activated. (more likely with opiate administration that rapidly crosses the blood brain barrier)

    Above usual dopamine results in Dynorphin elevation (and results in decreased numbers of dopamine receptors).
    Dynorphin inhibits dopamine release.
    Dynorphin elevation results in a drop in dopamine levels to below usual when the opiate level diminishes resulting in post use dysphoria. (and there are fewer dopamine receptors to respond to the lower level of dopamine)

    Dynorphin sensitizes the spinal cord to pain.
    Pain then increases to above usual when the opiate level diminishes resulting in rebound pain.

    Opiates dampen the effects of adrenaline.
    We compensate by increasing adrenaline levels.
    When the opiate level diminishes the increased adrenaline levels are uncovered and manifest as withdrawal symptoms such as anxiety, irritability, crawling skin (goosebumps), diaphoresis, nausea, and diarrhea.

    At higher doses and with some susceptible individuals the Opiate Induced Hyperalgesia is greater than the pain relief provided and the opiate causes pain to worsen (Classic OIH).

  2. Also, I agree with you that buprenorphine with or without naloxone is an excellent pain medication and that it is typical that after 6-8 weeks many to most chronic pain patients report better pain relief than with conventional opiates. I think that the agonist/antagonist action of buprenorphine provides a ceiling effect and that Dynorphin levels decrease to match this. This results in what I have come to call an “Analgesic Zone Migration”. Once this is complete most patients report excellent pain relief.

    It is also intriguing to think about kappa receptor effects.

  3. Our ability to pause and plan and to organize our intentions gives us the capacity of self-control. During states of urgency and extremes of euphoria, anxiety, or anger we do not have the time it takes to reflect and organize our responses to what is around us. Instead, we react quickly and often out of habit. When we use an opiate (that imitates endorphin), we are altering our stress response modulation system. We then enter a state where we are more likely to experience states of euphoric disinhibition or to have uncontrollable states of anxiety and anger.
    The repeated use of an opiate results in diminishing euphoric effects and increasingly dysphoric after effects. Over time the person is compelled in a Faustian bargain to keep using the opiate to manage and control their states of severe anxiety and irritability. It is not that they are unable to control their use of an opiate, it is that opiate use is necessary to control their irritability, anxiety, and dysphoric lack of energy and motivation and that they have no choice to do otherwise.

  4. I have been a chronic pain patient for close to 25 years. Last year my doctor decreased my morphine dose to be in compliance with the new Cdc guidelines. This happened over the period of 8 months and I was having trouble with withdrawal symptoms. I was offered clonidine and nothing else. I didn’t want to be in trouble with my doctor for noncompliance so I signed myself into inpatient rehabilitation. I went into withdrawal and was given buprenorpine. I was continued on Subutex outpatient. After 2 months I began to notice a decrease in my leg pain. I have a 2 level lumbar fusion since 1995 and have has severe pain in my back and referred down my legs. I used to have steroid injections to get relief. Now after 4 months on buprenorpine therapy I have no more leg pain. I have localized pain in my back and neuropathy in my feet,but even some of the back pain has been reduced. I am walking 2 miles 6 times a week now and feel 20 years younger. I will never use morphine again. One problem is with getting Subutex for pain. I have to do the addiction counseling thing and I’m not the typical addict. I never had the payoff of a high off of morphine because I was taking it as directed. It wouldn’t be logical for me to go back to taking it since the control my pain is better with Subutex, but I’m lumped into the addict category. I didn’t get thrown out of the pain clinic I used for 17 years and could go back any time I wanted to but for obvious reasons won’t. Why isn’t buprenorpine used in pain clinics as well as in addiction therapy?

    • There are some doctors using it, and I think that will increase going forward. One problem is that the various forms of buprenorphine are more expensive than ‘plain old agonists’ like morphine and oxycodone, so insurers fight paying for them. If I prescribe buprenorphine meds for pain, insurers deny coverage, saying that I should instead use a cheaper alternative like oxycodone. There is also some confusion out there, with some doctors thinking incorrectlyl that they cannot use Suboxone or Subutex for pain. They could, and that wouldn’t even require the special certification. The buprenorphine certification is only needed to use buprenorphine meds to treat addiction– and ANY doc with a valid DEA registration can prescribe buprenorphine for pain treatment.

  5. Interstitial cystitis should be on your list.
    With generic competition to Suboxone, there’s no economic incentive for pharma to get a pain indication approval for plain old sublingual buprenorphine. If nobody makes money, the very important story of buprenorphine for pain remains untold.

  6. I have been given Suboxton for pain. I’m going on month two so far Ssi has paid for this. My doctor thinks I may end up in counseling which as the above poster says she’s not an addict neither am I. Although the pharmacy told me that “I should not use my next dose of Herion” which I never have tryed. I love the stereotypes. And she imbarrassed me bad!!! How ever I don’t care who you are once you take an opiates for more then a week you will feel withdrawls. I have been on pain meds 21 years and now feel wonderful. Except for these SWEAT episodes. Only when I take my subs. Why is that. Which actually is why I am here looking for an answer. Anyone else experience this please feel free to drop me a note. And I’m 57 and have been thru the change of life in 2000 I was put there by hysterectomy…Help me Mr. Wizard…

    • Mr Wizard…. wasn’t there a guy on Saturday TV in the 1960’s by that name? Yes, there he is: http://philosophyofscienceportal.blogspot.com/2008/04/mr-wizardmissed-mentor.html

      Thank heavens for Google!

      Sweats are common with opioids. They are triggered during withdrawal, but are also common during opioid effects from any opioid drug or medication. People notice them more with methadone and buprenorphine, I suspect mainly because there aren’t other things– like being ‘high’– to notice. Sweating is by far the most-common complaint that I hear about from my own patients.

      Meds don’t work well for sweats, and you wouldn’t really want them to, as that would put you at risk for hyperthermia on a warm summer day. But people find some relief by doing something to create a ‘chill’, as soon as the hot flash starts. If you are carrying a cold beverage, touch it to your neck. Or carry a damp cloth in your back pocket, and touch that to your neck, or some other sensitive part of the body. If you have access to a sink, run cold water over the backs of your hands. If you have A/C in the car, turn it on full blast, and direct it to your face.

      There aren’t any great solutions, though. If you figure something out, please let me know!

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