Long-Term Opioid Analgesia Without Tolerance, Respiratory Depression, or Euphoria

I have been kicking these observations around for the past year, and have been unable to find a big fish willing to 'bite'. I truly believe that the observations below have the potential to dramatically change the approach to opioid treatment of chronic pain. Since I have a blog, I have a soapbox-- so I'll share the idea, and welcome comments in return. I do ask that proper attribution be provided if this article is shared.

Introduction:

Long-term opioid analgesia without tolerance, respiratory depression, or euphoria? Introducing the Holy Grail for chronic pain treatment!

Premise:

The miracle of opioid pain relief is fatally limited by tolerance, addiction and respiratory depression. Buprenorphine, when combined with a mu agonist, results in game-changing effects. Patients experience potent, dose-related analgesia from the agonist, but have NO euphoria. The therapeutic window is widened. Patients unable to control their use of a mu agonist alone gain that control when on buprenorphine. And most exciting, buprenorphine indefinitely anchors tolerance, maintaining analgesia WITHOUT DOSE ESCALATION. This finding offers huge implications for pain management.

Discussion:

Use of opioids for chronic pain has severe limitations. Tolerance removes the benefits of opioid analgesics over time. Worse, tolerance is associated with dependence and withdrawal. Many patients use additional doses of their prescription early in the month, then suffer through withdrawal while awaiting refills. Others find opioids through less-reliable, non-clinical sources.

At the same time, addiction to mu opioids is a nationwide epidemic. Reformulation Oxycontin has pushed many opioid users toward diacetylmorphine-brand name Heroin. Some physicians recommend avoiding mu opioids altogether for chronic pain (e.g. Physicians for Responsible Opioid Prescribing), while pain treatment advocates argue to ease narcotic restrictions.

Over the past six years I have treated over 500 patients using buprenorphine, mostly for opioid dependence. Buprenorphine, a partial mu agonist, is the active ingredient in Suboxone, a medication used for treating opioid dependence. The majority of my patients began their addictions with narcotics prescribed by doctors for back pain, knee pain, shoulder pain, fibromyalgia, chronic headaches, and other conditions.

Many of my patients found their pain reduced or gone after stopping mu agonists and substituting buprenorphine. Buprenorphine has the mu activity of 40 mg of daily methadone, but this activity is unlikely responsible for significant analgesia, since patients rapidly become tolerant to the agonist actions of buprenorphine. Instead, their pain while on mu agonists was likely maintained by psychological forces.

Patients on buprenorphine occasionally need opioid analgesia, just like other patients. My patients have had knees replaced, gallbladders removed, hysterectomies and c-sections, rotator cuff repairs, and in two cases, cardiac surgery. In all cases, sufficient analgesia was provided by maintaining daily buprenorphine at 4-8 mg per day, and using potent mu agonists, usually oxycodone, in doses ranging from 15-45 mg every 4-6 hours as needed.

Several patients have severe chronic pain from avulsion of the brachial plexus, failed spinal fusion, or other conditions, where prior opioid use resulted in rapid tolerance that prevented effective analgesia. These patients are now successfully maintained on combinations of buprenorphine plus mu agonists.

The combination of buprenorphine plus mu agonists has provided perioperative analgesia for patients on buprenorphine. Patients universally describe adequate pain relief, even after major surgeries. They also described the absence of euphoria, and to their surprise, the ability to control their use of pain medication-something impossible before taking buprenorphine.

But it is the effects on chronic pain that suggest a 'game-changer' for pain treatment. Even after over a year on combination buprenorphine/oxycodone, my patients 1. have no euphoria; 2. are often able to manage their own narcotic medication; and most important, 3. describe stable analgesia WITHOUT agonist dose escalation.

The ability to treat pain long-term without tolerance or dose-escalation is as exciting a development as was the initial discovery of opioids for pain relief!

Properties of a combination agent

Buprenorphine is administered sublingually, and could be prescribed as a separate medication, and use verified through urine monitoring. But greater safety benefits would come through regulations requiring buprenorphine (or a similar partial agonist) to be an inseparable part of every opioid prescription. Such a policy would dramatically lower the addictiveness and reduce the respiratory depression of mu agonists WITHOUT removing efficacy. The most obvious formulation would be a transdermal system that delivers buprenorphine and fentanyl, since both are already available in separate transdermal systems.

There may be situations, for example hospice care, where euphoria would be a desirable part of opioid treatment. But for other cases, analgesia without euphoria has obvious benefits.

I have written to several pharmaceutical companies with this idea, and have heard back that while the idea is interesting and scientifically sound, the generic nature of the component medications reduce the potential for profit that would motivate development. But given the potential value of this approach for multiple problems-- addiction and chronic pain among them-I have to think that there is money to be made-not to mention the advances in treatment that the approach offers.

Reference:

Some supporting background information can be found in: Alford, D., P Compton, and J Samet, Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy. Ann Intern Med. 2006 January 17; 144(2): 127-134.

I also discuss this approach to pain treatment in my 'Users Guide to Suboxone', sold on Amazon and at bupeguide.com

Jeffrey T Junig MD PhD

Please do not reproduce without attribution.