Wednesday, April 6, 2011

Is Buprenorphine Effective for Chronic Pain?

 By guest author, Dmitry M. Arbuck, MD

The transdermal buprenorphine (Butrans®) patch became available in the United States in early 2011 as 5, 10, and 20 mcg/hour doses to be delivered over 7 days [info here]. Since 2001, buprenorphine also has been available in most European countries as Transtec® in 35, 52.5 and 70 mcg/hour transdermal patches that deliver the dose over 96 hours [info here]. Transdermal buprenorphine is approved and indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.

Sublingual buprenorphine formulations, which are FDA-approved for the treatment of opioid addiction, have been prescribed off-label for the management of chronic pain since they became available in 2002. These come in a pure buprenorphine formulation (Subutex®) and a buprenorphine-plus-naloxone combination (Suboxone®) [info here].

Unique Properties of Buprenorphine

Buprenorphine is a unique opioid with mu-receptor agonist and kappa-receptor antagonist properties. Confusion about the agonist/antagonist properties has caused concern in many prescribers and made them reluctant to use this molecule for the treatment of pain. It may be more appropriate to classify buprenorphine as a partial agonist, which might decrease apprehensions about any antagonistic or blocking function on the mu-receptor.

Buprenorphine has a higher affinity for the mu-receptor than regular opioids; therefore, if pure mu-agonists are already present in the patient, the introduction of buprenorphine displaces existing opioid and may precipitate acute opioid withdrawal. Conversely, when the buprenorphine molecule is already bound to the mu-receptor, it does not readily dissociate on introduction of a regular mu-agonist; therefore, adding another, regular opioid on top of buprenorphine to help control pain does not produce opioid withdrawal symptoms. This phenomenon dictates a specific approach for the initiation of buprenorphine treatment (described below).

It could be contended that, due to the large number of identified mu-opioid receptors, no particular opioid binds to all of the receptors. This may be the rationale for combining different opioids in the same patient or combining buprenorphine with a regular mu-agonist for added pain relief.

The half-life of buprenorphine ranges between 20 to 73 hours, but its pain-relieving properties last on average 6 to 8 hours. Hence, the most-prescribed regimen of buprenorphine in pain management is twice daily (b.i.d.) to four-times daily (q.i.d.). In principle this does not differ from methadone, which has a half-life of 24 to 36 hours and a typical elimination half-life of 15 to 60 hours. In spite of these lengthy times, the pain-related properties of methadone actually are short lived and typical dosing regimens in pain management are three to four times daily.

As with methadone, buprenorphine is metabolized by the cytochrome P450-3A4 enzyme system. This calls for special care when combing buprenorphine with potent CYP-3A4 inhibitors like fluvoxamine, ketoconazole, grapefruit juice, methadone, and others that might increase buprenorphine blood levels. In contrast, phenobarbital and Tegretol® (carbamazepine), as well as smoking, may theoretically decrease buprenorphine blood levels and its analgesic properties by increasing its metabolism via induction of CYP-3A4 enzymes.

Analgesic Benefits of Adding Opioid Antagonists

There is mounting evidence that ultra-low doses of opioid antagonists — specifically naloxone or naltrexone — may augment the analgesic properties of opioids, including buprenorphine. We have observed in our practice that buprenorphine monotherapy (Subutex or Butrans patch) provide less robust pain control than the buprenorphine-naloxone combination (Suboxone). This is sufficiently noticeable clinically that we usually combine micro-doses of oral naltrexone with buprenorphine patch therapy. In the case of Suboxone, the absorption of the naloxone component is poor and produces sufficiently low blood levels of the opioid antagonist that it enhances rather than interferes with buprenorphine pain management.

In conjunction with the buprenorphine patch we prescribe a liquid oral naltrexone formulation in a dose of 1 to 8 mcg per day. This formulation is prepared by compounding pharmacies and costs between $30.00 and $40.00 (USD) per month, which frequently is an out-of-pocket expense for patients since it is usually not covered by insurance plans. Nonetheless, many patients in our practice experience enough benefit of this combination that they are willing to invest in this add-on medication.

Unlike buprenorphine, naloxone and naltrexone antagonize both the kappa and mu opioid receptors. However, opioid antagonists available in the U.S. (naloxone and naltrexone) have a high affinity to the excitatory rather than inhibitory side of mu-receptors; therefore, they potentially decrease development of tolerance and improve pain control.

Buprenorphine Induction

A key factor for successfully converting patients from regular opioid analgesics to buprenorphine is the way it is started — induction. In clinical practice, emerging symptoms of opioid withdrawal are the best indicator that it is safe to start buprenorphine. Withholding long-acting opioids for 3 days and short-acting opioids for 24 hours is sufficient to prevent severe withdrawal symptoms when buprenorphine is initiated in the majority of patients. We have developed a buprenorphine induction system that works for the majority of our patients:

  • We start Suboxone while the patient is in the clinic under a nurse's observation.

  • If the patient has abstained from opioids for the required time — 3-days for long-acting opioids, 24 hours for short-acting opioids — we give a test dose of 1 mg of Suboxone to most patients and 0.25 mg of Suboxone to frail or elderly patients.

  • If the patient is in acute opiate withdrawal, we initially provide a 2 mg dose of Suboxone, with additional doses if there is worsening of withdrawal, possibly precipitated by the Suboxone itself.

  • If the Suboxone dose is tolerated, the patient is instructed to take the same dose in eight (8) hour intervals the day of start-up.

  • Patients are scheduled for a follow-up appointment the day following induction, and we double the start-up dose if pain is not controlled

  • During the first week, the patient has the flexibility of adjusting the dose depending on their response and side effects. The patient is instructed to either continue the established dose if it is clinically effective, or to decrease or increase the dose depending on side effects versus benefits. A follow-up appointment in one week is scheduled to fine tune the dose of Suboxone.

As mentioned above, we instruct patients to abstain from all opioids before the start of buprenorphine. In patients on high doses of opioids (more than 100 mg of morphine equivalent per day) inpatient detoxification is usually required. Patients on less than 100 mg of morphine equivalent per day, or very motivated patients on higher doses, who are able to abstain from opioids for the required time may be started on Suboxone or Subutex on an outpatient basis. As an adjunct, tramadol may be used for breakthrough pain during the 24 hours before starting Suboxone, since tramadol does not seem to be associated with withdrawal symptoms when buprenorphine is added.

The most frequent continuing dose of Suboxone in our patient population is 12 mg/day in divided doses, but doses range widely from 0.5 mg/day to 8 mg four (4) times daily (32 mg/day total). We have observed patients needing less than 0.5 mg/day to more than 32 mg/day of Suboxone for good pain control. Generally, buprenorphine doses greater than 32 mg/day sublingually do not produce added analgesic benefit, but we have observed exceptions to this rule.

We have not seen a correlation of adequate buprenorphine analgesic dose with patient age, gender, or previous doses of opioids. Patients who could not control their pain with high doses of regular opioids may end up being well controlled on small doses of buprenorphine, and vice versa. We cautiously inform patients on the day of buprenorphine induction that we do not expect pain control the very first day; rather, the goal is avoidance of side effects. If side effects are controlled, we titrate buprenorphine upward to an appropriately individualized dose.

Managing Buprenorphine Side Effects

There are a number of potential side effects associated with buprenorphine therapy that should be considered:

  1. The most common side effects of buprenorphine are nausea and vomiting, with onset frequently in 2-3 hours after the initial dose of Suboxone. We provide patients with antinausea medications, including promethazine (Phenergan®) and/or ondansetron (Zofran®). If they have continued nausea, we recommend taking antinausea medications on a scheduled basis. In our experience, changing Suboxone to the oral route from sublingual administration does not noticeably decrease analgesic efficacy but it does significantly decrease the occurrence of nausea.

  2. Constipation is highly prevalent with buprenorphine and patients routinely are started on a combination of a laxative and stool softener — Senokot-S® (a natural vegetable laxative plus stool softener) being most commonly used. Urinary retention is common and counteracted by prescribing bethanechol (eg, Duvoid®, Urecholine®).

  3. Headaches are observed with some regularity and this side effect can occasionally be difficult to control. Nonsteroidal anti-inflammatory drugs (NSAIDs) are sometimes effective, but we have seen a number of patients who had to stop buprenorphine because of uncontrolled headaches.

  4. Lower leg edema is not uncommon in patients taking buprenorphine. It seems that switching from the buprenorphine-naloxone combination to buprenorphine monotherapy decreases this side effect; however, in other patients the exact opposite works. The addition of ultra-low doses of naltrexone to buprenorphine formulations (including Suboxone) helps to resolve lower leg edema.

  5. Itching associated with buprenorphine therapy, which is not commonly observed, responds to diphenhydramine (Benadryl®) or hydroxyzine (Vistaril®).

  6. Buprenorphine sometimes causes intractable insomnia and this side effect is at times difficult to control. We have had a number of patients needing to discontinue buprenorphine because of uncontrolled insomnia.

  7. We also have encountered a number of patients complaining of subjective problems with breathing. Although there has been no life-threatening respiratory depression in our patients, several had to stop buprenorphine because of discomfort with breathing. Surprisingly, this discomfort might occur even in patients who do not experience this on high doses of regular opioids.

  8. Another surprising clinical observation is that there appears to be no correlation in a given patient between their previous dose of opioid analgesic and the therapeutic dose of Suboxone. We have had multiple patients on high doses of opioids — for example, 600 mg/day of Oxycontin®, 300 mg/day of methadone, etc. — who, after being switched to buprenorphine, had good pain control with only 6-12 mg or less of Suboxone per day in divided doses.

Buprenorphine Transdermal System (Patch)

Butrans, as much as Suboxone and Subutex, seems to be especially effective in neuropathic pain. We also successfully use buprenorphine in treating musculoskeletal, visceral, and cancer pain, as well as for chronic headaches. Pain is a syndrome and regardless of its causes, it responds to treatment with buprenorphine. Furthermore, possibly because of kappa antagonism, buprenorphine seems to have robust antidepressive and antianxiety properties, which also helps in pain management.

In our experience, buprenorphine patches in the existing doses of 5, 10, and 20 mcg can be insufficient to control pain in some patients, and attempts to convert them from Suboxone to Butrans fail due to inferior analgesia compared with sublingual buprenorphine. It seems that the 20 mcg Butrans patch is roughly equivalent to 12-16 mg/day of sublingual buprenorphine; hence, the 20 mcg patch may provide inadequate pain control for patients who would require doses greater than 16 mg/day of buprenorphine sublingually.

At the same time, the 5 mcg buprenorphine patch may be too high an initial dose for frail, elderly, or otherwise sensitive patients. Because of this, we routinely start patients on Suboxone and then try to convert them to the Butrans patch if it is tolerated. It is not that uncommon for our patients to be on a combination of the Butrans patch and Suboxone in an attempt to increase the total daily dose of buprenorphine.

It seems that buprenorphine in sublingual or transdermal forms produces less “liking” and therefore presents less of a risk for developing abuse and addiction. This notion prompted us to start using buprenorphine as a first-line analgesic in patients with moderate to severe chronic pain.

If it is necessary to withdraw patients from buprenorphine the same care should be taken as with any other opioid. It is actually easier to discontinue buprenorphine than full mu-agonist opioids. The majority of patients spontaneously decrease their buprenorphine dose after sustained pain control is achieved for a few months; in contrast, only a minority of chronic pain patients on regular opioids tend to do this. At the same time, there is a small subgroup of patients who may develop significant withdrawal symptoms when they attempt to discontinue buprenorphine on their own.

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About the Author: Dmitry M. Arbuck, MD, is a psychiatrist specializing in pain management. In 2000 he started Meridian Health Group, a pain management practice that grew into a multidisciplinary pain management facility treating all types of chronic pain. He also has an appointment as a volunteer Assistant Professor of Psychiatry and Medicine at Indiana University School of Medicine and is the former president of the Russian American Medical Association. Dr. Arbuck has served on the speakers’ bureaus of AstraZeneca, Cephalon, Forest Laboratories, King Pharmaceuticals, Metagenics, Pfizer, Reckitt Benckiser, and Sanofi. For more information, you can e-mail Dr. Arbuck at darbuck@meridianhealthgroup.com, phone him at 317-814-1000, or visit his clinic website at: www.meridianhealthgroup.com.

Proviso: Facts, advice, and opinions expressed above are those of the guest author. Pain Treatment Topics does not endorse or promote the off-label prescribing of any medications. These UPDATES are supported in part by an unrestricted medical education grant from Purdue Pharma LLP, a manufacturer of Butrans and Senokot-S, which had no role in suggesting, developing, or reviewing this article.

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10 comments:

docpatmac said...

I commend you on a very thorough assessment of the Buprenorphine/BuTrans use in chronic pain. There are a couple things I might add if you don't mind. Subutex/Buprenorphine is available as a generic, made by Roxxane, at about a fourth of the cost of the name brand. The drug Suboxone is extremely expensive, running about $6.75 per tablet on average, the BuTrans patch likewise is running on average $85.00 per patch. The generic Buprenorphine is about $2.50 per sublingual tablet. I am a retired APRN, and keep up with all the latest research through this and many other sources.

I mention this because I was myself switched from Kadian to Suboxone earlier this year, with only minimal improvement, and in doing my research found that the Naltrexone component quite possibly was blocking the therapeutic effects of the bupe. My pain management doc and bupe doctors agreed.

After some back and forth with the insurance company, was finally approved for the generic buprenorphine and the BuTrans 20 mcg. patch a few months ago. That change made all the difference. My pain level which never got better than an 8 out of 10 on agonist opiates, but went down to a FIVE on the combination therapy! And my functionality increased fourfold. Amazing! The side effects are quite minimal when compared to the Kadian, which caused severe constipation, dry mouth, urinary retention and sedation. On Bupe, I have almost NO sedation, and after three years of not feeling much of anything, I'm amazed at all that I've missed emotionally. I'll take the mild constipation, the other very minimal s/e's, just to start feeling something again.

Not to say other people will have the same or even close to the same response as I did, but it certainly bears out the conclusions of many studies. Hopefully more studies will be done.

Cecylia Bryan said...

Great topic!! In this issue I always appreciate that Buprenorphine effective for Chronic Pain. Thanks for letting us the briefings. Thanks!

Allyson J. said...

The response has largely I think, to do with how and why this is used, in what dose, and with what therapies.

As a sufferer of Complex Regional Pain Syndrome, I thank you for an HONEST (not doctored look, to get the answers perhaps that one searches for: it is more for a humble approach that God, uh, like maybe we can start chasing something recent research shown. As my CURRENT provider said, "Only would the arrogance of modern medicine think they can tie up something as complex as pain in one fell swoop of ketamine (which is originally a veterinary tranquilizer, and though it has a rap, and I know that not everyone has the same opportunties, then I would call it equality in health care. But RSD violates so many natural and laws of God, that I don't think people can be criticiized for availing themselves of what is there.. This is from a 'former RN" who let her license lapse; but now wants to work in hemp; I feel useful there. I was having my hands tied in nursing. But whole lot of doctors. THEN I WAKE up with this in an ICU, and whamo, sOL, kiddo, and btw, you are a drug addict.

I got legal and only use Rick. Natural? So disagree with me and don't post this, I don't rightly care. But I am tired of physicians who take 2 insurances.

Visa/MC
Cash.

Enough said. I left the world of "pain mis-management' while it was good. That is what makes you spit your teeth out. Before 40, if you have had it for 30 years already.

thanks!

Anonymous said...

I have been using Bu-trans patches for chronic low back pain for over a year 10mcg and also getting cortizone shots. I started the patch 7 months before the shots and it brought my pain level from a 9 or 10 to a 7 or 8 then the shot brought it down to a four of five. this is good , I know but still can't seem to find anyone who wants to fix the problem rather then cover up the symptoms. P.S At the start of using the patch I had severe vomiting which I found very difficult as I still could not bend at that point

Bethy said...

I am in the process of trying to withdraw from the Butrans patches. Have been on 10mg. For 6mo now. Dr. just decreased me to 5mg and so far I am doing ok-mild sxs. I have fibro,just FYI.My concern is when I go cold turkey from 5mg to nothing. Any suggestions on something he could put me on temp.tohelp?

SB. Leavitt, MA, PhD said...

We wish you well, Bethy, in your discontinuation of the medication. However, this is not the place to seek medical advice. Your doctor is the best one to offer suggestions.

Jim Lacey said...

Dr. Leaving,

Are you guys aware of any PMDs in the northern VA or DC area? I have been looking for someone that practices your methods in my area and all I can find are detox doctors.

Thank you.

SB. Leavitt, MA, PhD said...

Mr. Lacey, I'm not sure what you mean by "practices your methods"; however, we do not recommend any specific practitioners at this site. Sorry.

Terry Beckham said...

I recently switched from suboxone to generic subutex. About one hour after my first dose, (1/2 of a 2mg pill) I felt a little itchy and kind of prickly-like.

This went away, but 2 weeks later, I developed a bad case of pruritus, and had to get a script of Clobetasol. This helped a lot and the severe itching stopped. I discontinued the clobetasol, but the itching has returned.

It is bad on my back side, feels like poison oak, and then I have the prickly-stingy itch all over my body. Could this be caused by the generic subutex? I cannot afford the name brand or the name brand of suboxone.

Can anyone perhaps shed some light on this matter for me? I cannot even think about switching to a class 2 drug!

Terry

Blane said...

hello,i had lower back surgery in 2006 on 4 levels of my spine i was put on 20mgs of methadone pr day and i must say it worked on killing the 8 out of 10 pain i was having at that time,in 2013 i was put on buprenorphine 2mgs x 2 per day,all though it seems to work some what for about 7 hours!it's not at all as strong as as methadone,i think its more for the doctors sake than any thing because its only a class three and not a class two drug!its easy to call the rx in over the phone with no office visit needed