Imagine bringing a patient to surgery on a naloxone (Narcan®) intravenous continuous infusion that you cannot stop for at least 2-3 days post-operatively. Envision trying to treat that severe pain with acute opioid therapy (aAOT) but that with each sequential dose escalation, your attempts remain futile because naloxone is blocking the AOT from combining at the site of action, the mu-2 opioid receptors. Essentially, this is what’s happening when you perform surgery on a buprenorphine (Suboxone®) patient, but with some inherent analgesia activity from the buprenorphine.
Make no mistake; in this case, the adjuvant therapeutic options (regional nerve blocks, IV acetaminophen and ibuprofen, pregabalin, SNRIs, etc.) become the principal analgesic treatments, and AOT becomes the adjuvant – exactly opposite to what we’re all used to. [aAOT examples include morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, and others.]
One of the most misunderstood opioids among clinicians is buprenorphine, and even more especially when combined with naloxone in the branded form of Suboxone®.
If a patient has a scheduled or elective surgery with an active prescription for any buprenorphine product, the approach is not too difficult, but it requires an understanding of pharmacology, rational polypharmacy, but most importantly, common sense.
If the patient arrives on site in an emergency situation with an active prescription for any buprenorphine, the approach is a bit more challenging compared to elective surgery.
But before traveling down this road, let’s first ask; what compelling justification is there for combining buprenorphine with naloxone in the first place? Answer: NONE! Consider that buprenorphine is 90-95% bound to mu-1 receptors and has a superior binding affinity compared to naloxone. Even the manufacturer (Reckitt Benckiser) admits to this, as seen in a 2004 Johns Hopkins University School of Medicine writing entitled “Practical Considerations for the Clinical Use of Buprenorphine“.
How then did Reckitt Benckiser ever convince the FDA that this is a necessary or safer combination compared to buprenorphine alone? I would sure like to know the answer to that looming question if anybody can enlighten me. Dr. Hendrée E. Jones shares a diagram that is ironically referenced to the eminent Suboxone manufacturer, Reckitt Benckiser. It actually illustrates how and why buprenorphine is more tightly bound to the mu-1 receptor compared to naloxone.
In fact, van Vorp and colleagues demonstrated this well showing that although naloxone can reverse burpenorphine, the naloxone dose must be huge and continuous. But even then, the reversal is short-lived.
You can’t have it both ways folks; either naloxone reverses buprenorphine or buprenorphine blocks naloxone! Here’s the figure from Jones’ writing with italicized dialogue from his article.
Heroin, Buprenorphine, and Naloxone Effects at the Mu Opioid Receptor
Heroin, buprenorphine, and naloxone (represented above by blue polygons) produce contrasting effects because they interact differently with the brain’s mu opioid receptors (red pentagons).
First, the chemicals differ in how much each stimulates the receptors (represented above by the percentage of receptor “activity zone” each fills). The stronger the stimulation, the more pronounced will be the opioid effects of pain relief, feelings of well-being, respiratory depression, and so on. Heroin, classified as a full receptor agonist (stimulator), nearly fills the activity zone. Buprenorphine, a partial receptor agonist, fills a smaller portion of it. Naloxone does not stimulate the receptor at all.
Second, each chemical binds to the receptors more or less strongly (represented above by the percentage of receptor “affinity zone” it fills). A chemical that forms a tighter bond can push one with a weaker bond off the receptors and take its place. Thus, buprenorphine can push heroin off the receptors, and in doing so replace heroin’s full receptor stimulation with its own partial stimulation.
Buprenorphine also binds more tightly than naloxone. Naloxone can compete with heroin for the receptors. Because naloxone can block heroin and other opioids from stimulating the receptors while not itself stimulating them, it can precipitate opioid withdrawal and is classified as an opioid receptor “antagonist.”
The buprenorphine/naloxone mixture in Suboxone is touted to reduce the possibility of illicit use by injection if an attempt is made to abuse the Suboxone by a parenteral route, presumably because “naloxone antagonizes the opioid effect”. This justification is flawed.
Let’s think about this for a minute…
Repeat after me…at normal therapeutic doses, naloxone will never see that mu receptor because buprenorphine has a higher binding affinity, a longer half-life, and therefore naloxone is not capable of reversing it. In fact, to the contrary, it’s more believable that buprenorphine could reverse naloxone.
Now that we’re past that mess, let’s figure out what to do for our surgical patients in a stepwise approach while considering the dialogue outlined above.
Emergency surgery for the patient on buprenorphine comes with challenges for sure. In a letter to the editor entitled “A new pattern of buprenorphine misuse may complicate perioperative pain control“, Marcucci and colleagues point out just how disastrous this can be.
I ask you to note the following…
- Buprenorphine in the form of Suboxone® has a half-life of 24-42 hours. Following surgery, pure opioids will not be able to displace the buprenorphine for up to 5 days because of the long half-life.
- Intuitively, clinicians might keep dosing AOT such as morphine, hydromorphone, or oxycodone in an effort to achieve analgesia, while all the while their efforts prove largely ineffective at normal doses because these drugs need to hover over the site of action until small amounts of buprenorphine leave their binding site. The patient remains in pain, but moreover the patient is tolerating all these opioids with repeated and escalated doses just fine.
- Hours later the buprenorphine begins to dissociate from the mu receptors and now all of the administered pure agonists listed above rush for the receptors. The worst possible outcome here would be respiratory depression and death.
Certain literature (available upon request) misinterprets previously published recommendations and makes the leap that methadone 30-40mg/day could be used in the acute surgery setting to replace buprenorphine. Are you kidding me? The methadone could stay around for quite some time (half-life of 10-60 hours)…just enough time to cause significant toxicity as the buprenorphine wears off. Others say use hydromorphone by continuous IV infusion. Are any of these suggestions clinically proven in double blind studies with an outcomes assessment? Not that I know of.
My [clinically unstudied and unproven] suggestion is to use a highly potent pure opioid with similar lipophilicity that has a short half-life. It seems reasonable therefore that there could be some competition between fentanyl and buprenorphine. But the beauty here is that fentanyl has a short half-life and the patient can be supported medically for the short duration while fentanyl is metabolized, should we overshoot the mark while buprenorphine stops lingering on the receptors.
Depending on the complexity of the surgery, another practical approach would be to use buprenorphine intravenously at a starting dose of 0.3mg every 6-8 hours. Unfortunately, probably 99.9% of U.S. surgeons have little to no experience with IV buprenorphine (but to be fair, neither do pharmacists). Remember, since buprenorphine is a partial agonist/antagonist, its analgesic properties eventually plateau and no more analgesic benefit will be seen even with escalating doses.
What about scheduled or elective surgery for patient on buprenorphine?
Be smart and wean the patient off buprenorphine and onto a pure opioid beginning 2-4 weeks prior to surgery. You will make everyone’s life easier; patient and clinicians.
And finally, it is a bad idea to continually dose the ambulatory surgery patient with pure opioids per standard surgical orders immediately post-op if they were on buprenorphine, because pure opioids will not make it to the mu-1 receptors. Upon hospital discharge, AOT may finally get to the receptors when the patient is home and unsuspecting. Or, I have seen scenarios where the patient is sent home with oxycodone, hydrocodone, morphine, or others, and told to resume their buprenorphine…and the patient wonders why their pain isn’t controlled. That is a simple answer; the buprenorphine is blocking the pure opioid agonists from getting to the mu-1 receptors as I clarified earlier.
I encourage clinicians to engage ii studies to validate a stepwise approach to treating surgical patients that have active prescriptions for buprenorphine. For now however, the bottom line is…USE COMMON SENSE!
PLEASE tell us how you handle these patients if you are a clinician. For patients, we sure would be interested to learn of your surgical experiences. Also, tell us if you’ve seen disasters because of the issues outlined above. All comments are welcome!
- Alford DP, Compton P, Samet JH. Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy. Ann Intern Med. 2006 January 17; 144(2): 127–134.
- Heit HA, Gourlay DL. Buprenorphine New Tricks With an Old Molecule for Pain Management. Clin J Pain February 24; (2): 93-97.
- Jones HE. Practical Considerations for the Clinical Use of Buprenorphine. Science & Practice Perspectives. 2004 August; 4-19.
- Marcucci C, Fudin J, Thomas P, et al. A new pattern of buprenorphine misuse may complicate perioperative pain control. [Case Reports, Letter]. Anesth Analg 2009 Jun; 108(6):1996-7.
van Dorp E, Yassen A, Sarton E, Romberg R, Olofsen E, Teppema L, Danhof M, Dahan A. Naloxone Reversal of Buprenorphine-induced Respiratory
Depression. Anesthesiology 2006; 105:51–7.