Embracing a New Medication Option

In October 2002 the Food and Drug Administration (FDA) approved Subutex and Suboxone for treatment of opioid addiction. These sublingually administered formulations of the partial opioid agonist buprenorphine were the first medications for opioid dependence since methadone and LAAM. The new drugs have been recognized as having the potential to transform the way opiate addiction is treated in the United States. Because our facility, Bowling Green Brandywine (BGB) in eastern Pennsyl-vania, has been a leader in the development of inpatient treatment strategies for opioid dependence, we clearly needed to investigate these new agents' implementation.

Subutex is the sublingual form of buprenorphine alone, while Suboxone consists of buprenorphine and naloxone in a 4:1 ratio. Naloxone, an opiate blocker, is added to eliminate potential for abuse of buprenorphine itself (i.e., by crushing and injecting it). Suboxone was developed for use in office-based outpatient treatment. Because we felt that BGB's highly structured residential environment would preclude abuse, we chose Subutex for our program. Both medications are available in 2 mg and 8 mg strengths and are marketed exclusively by Reckitt Benckiser Pharmaceu-ticals, Inc.

Buprenorphine acts as a partial agonist with high affinity and low intrinsic activity on certain opioid receptors (mu receptors). It acts as an antagonist, or blocker, on other receptors (kappa receptors).1 What this means for opiate-addicted patients in acute withdrawal is that, when given buprenorphine, they will experience relief of their withdrawal symptoms without the euphoria and sedation of a full opioid agonist such as methadone.

Buprenorphine has a mean half-life of 37 hours, allowing for once-daily dosing. Our review of the literature told us that patients who received this medication in the morning would not doze through the meetings and lectures that form the basis of our clinical program. Methadone's sedating effect when used as a detox medication is of particular concern in light of ever-shortening lengths of stay for treatment as dictated by insurers and funding sources. With many patients' inpatient treatment limited to detox only, patients who are sedated during their detox lose much of the benefit that counselors and group therapies have to offer.

Methadone tapers in use at BGB start at a level largely based on the patient's history of drug use (supported to an extent by the urine drug screen). Since drug histories provided by patients arriving for treatment are notoriously erratic, we set out to make treatment with Subutex more interactive. We hoped to develop treatment protocols determined by the patient's symptoms, not by the declared amount of opiates used (which tends to be exaggerated) or the values returned from the lab.

We recognized that since office-based buprenorphine administration (with the Suboxone formulation) could represent the future of opioid maintenance therapy, exposure to Subutex while at BGB could help our patients assess whether it works for them. We felt that the better informed patients were about this new medication, the more likely they could benefit from it.

Clinical implementation

To initiate the use of Subutex at BGB, we needed to identify a subset of the incoming opiate-addicted population that would be small enough to manage effectively in terms of induction and dosing, and be most likely to benefit from a Subutex detox. We designated two groups as candidates for Subutex: all patients in treatment for their first opiate detox, and those with a history of dependence on prescription opiates only. We also included any patients who specifically requested Subutex (they either had prior experience with the medication or simply had heard about it).

Because buprenorphine has a higher affinity for opioid receptors and because it is only a partial agonist, even without naloxone added it can precipitate acute withdrawal if given to patients who already have opiates in their system.2 Dosing guidelines published by Reckitt Benckiser therefore recommend induction in small, incremental doses.3 In keeping with the pharmaceutical com-pany's general recommendation, we required a minimum of eight hours since last use of heroin, 12 hours since last use of OxyContin, and 24 hours since last use of methadone.

Patients were screened for disqualifying medical conditions, advised of the medication's side effects, given a printout of information about the medication, and started on a 4 mg sublingual dose of Subutex. Initially patients were told to return to the nursing department anytime between two and six hours after their first dose if they experienced any withdrawal symptoms. This was later simplified to, “Come back in four hours so we can see how you are doing.” Patients who reported any symptoms of opiate withdrawal after four hours received another 4 mg of Subutex.

On day two a nurse evaluated patients prior to dosing, using a tool we developed called the Subutex Protocol Withdrawal Assessment. This tool recorded whether the patient had been given a second dose of Subutex on the previous day, and evaluated his/her general physical condition both subjectively and objectively. Patients were asked to record how they felt (“OK,” “not so great,” or “terrible”); any reported or observed withdrawal symptoms including nausea, vomiting, stomach cramps, chills, body aches, runny nose, anxiety, insomnia, and agitation were recorded. Most patients who had not received a second dose during the induction phase were automatically given 8 mg on day two. Patients who had received 8 mg of Subutex during the induction phase were given 10 mg on day two.

On day three, patients again were assessed prior to dosing. Those who said they felt “OK” and denied any withdrawal symptoms were given 8 mg on day three and were subsequently tapered at a rate of 2 mg per day. All others were dosed with another 10 mg on day three and 8 mg on day four, and then continued on a 2 mg/day taper.

It should be noted that this dosing regimen evolved after considerable feedback from patients and the nursing staff. It is a general guide that has seemed to work for most patients. In some cases we modified the protocol to suit individual treatment needs. We also used Reckitt Benckiser's dosing guide to inform our decisions, and gathered clinical information from every facility we could find that was using Subutex at the time we started. We found that the approaches varied greatly across facilities.

Patients received, in addition to Subutex, what we call the opiate protocol medications on an as-needed basis for the duration of their detox taper and two days thereafter. These medications include ibuprofen (for pain), prometh-azine (for nausea), dicyclomine (for stomach cramps), and loperamide (for diarrhea). During the induction phase of their detox, all patients received a list of these medications with some guiding information. Although the evidence is purely anecdotal, it seemed that those patients who took advantage of these adjunct meds, especially during the first few days of detox, experienced less discomfort and had fewer complaints than those who did not use them.

For our nursing staff, the interactive nature of the Subutex protocol was confusing at first, since our tapers are usually written from day one, recorded in the medication administration record, and dispensed as written. Another adjustment had to be made in terms of dosing time. Patients on methadone simply come into the dosing room, drink their methadone, and leave. But patients on Subutex had to be evaluated and then had to sit without talking, under observation, for up to 10 minutes while the medication dissolved under their tongue. BGB's senior dosing nurse (with 20 years of addiction treatment experience) pointed out that although sublingual administration increased dosing time, it also provided an opportunity for patient-nurse interaction, counseling, and general support.

Subutex is considerably more expensive than methadone. Our wholesale cost for 10 mg of Subutex is $8, while our cost for the equivalent of methadone is 9 cents. However, BGB management made it clear from the beginning that cost should not play a role in our protocol for using Subutex. Whether cost becomes an issue at our facility in the future remains to be seen.

Results

On the last day of their dosing taper, all patients treated with Subutex were asked to fill out an evaluation. Over the course of our first 12 months of using Subutex as a detox medication (March 2004 to March 2005), we received 132 evaluations, revealing the following results:

• 105 of these 132 patients had zero or one previous detox treatment experiences.

• 59 patients self-reported mild withdrawal symptoms experienced during detox. Thirty-one patients reported moderate withdrawal symptoms, 26 reported severe withdrawal symptoms, and 16 reported no withdrawal symptoms.

• 54 patients reported having a previous detox experience using methadone. Comparing Subutex with methadone, 41 of these patients said Subutex was better or much better, 3 said it was worse or much worse, and 10 said the two medications' effects were the same.

The evaluation's comments section generated a wide range of responses, from “[Subutex] took the edge off physical sickness but all symptoms were still felt. [It] didn't help my cravings” to “Subutex works great. I hope it will take the place of methadone someday.” One patient in particular provided us with valuable insight into patient attitude and response to Subutex (see sidebar).

In addition to using Subutex as a first-line agent in opiate detox, we have developed another application for this medication. This occurred as a result of a request by a patient who had been maintained on methadone at BGB during the last six weeks of her pregnancy, had given birth to healthy twins, and had returned to our facility to detox from methadone. She had been on a split dosage of 130 mg of methadone during her pregnancy. She asked if she could be switched to Subutex toward the end of her methadone taper because she had done this previously and said it had worked well for her. It is important to point out that the FDA has not yet stated that Subutex is safe for use during pregnancy, although early research in this area has been promising.

Because of the patient's request, we have developed a taper-ending transition to Subutex for those patients detoxing from methadone maintenance. Although we are not sure why, we have observed that those patients who choose to end their taper with Subutex seem to experience less discomfort during the last few days of their taper and in the days immediately following. In the protocol we developed for the Subutex transition, the patient is tapered to 30 mg of methadone and held there for three days. Twenty-four hours after the last dose of methadone, the patient is given 4 mg of Subutex. Four hours after this first dose, another 4 mg is administered. On the next day the patient receives 12 mg of Subutex, and the dose is generally tapered by 2 mg each day thereafter.

We did not look to existing medication protocols in developing this regimen; we made the transition to Subutex because the patient asked us to do it and we thought it was an interesting idea. It has proven so successful that most patients detoxing from methadone maintenance in our facility ask to be switched to Subutex to finish their taper. This protocol works well, but some patients do experience moderate withdrawal symptoms on the day of transition to Subutex. Recently we have tried moving the first dose of Subutex to midday, so that there is closer to 30 hours between the last dose of methadone and the first dose of Subutex. So far this seems to work better.

Looking ahead

There is no question that adding Subutex to our armamentarium has improved patient care. We have expanded our criteria for using it to include detox for any patient admitted with a stated history of using five bags or fewer of heroin a day. We think, in fact, it could be used to detox patients who use up to 15 bags per day if the protocol were changed to include higher initial doses and a longer taper.

We have found that drug addicts, despite their seemingly reckless lifestyle, are often conservative in their approach to treatment. They tend to want to stick to what they know. Those who come in with prior experience with buprenorphine often request it for detox. Those who haven't heard of it are usually resis-tant to its use.

We also have found in the past year that more patients are admitted with a history of Suboxone maintenance therapy, although this treatment has usually been administered for less than one month. Cost is the reason most often cited for having stopped it.

The number of doctors in our area certified to prescribe Suboxone for maintenance therapy does not appear to have changed much in the past year. But patients in our area still have more opportunities to access Suboxone maintenance therapy than they did a year ago. Several local methadone clinics now offer it as an alternative to methadone. Patients still have to visit the clinic daily for dosing, and they earn take-home doses only after demonstrated compliance with the clinic's treatment program.

As we look ahead, our primary concern will be how to help those patients who, having been exposed to Subutex while at our facility, now want to investigate maintenance therapy on Sub-oxone. At present the best we can do is explain the approximate cost and that it is necessary to find a certified physician who has not reached his/her maximum allotment of 30 patients. Those patients not daunted by the cost are referred to SAMHSA's Web site and are guided through the physician locator list. (For more on federal government activity in this area, see www.samhsa.gov/ SAMHSA_News/VolumeXIII_5/article8.htm.)

This is in contrast to those patients who meet the criteria for and want to start methadone maintenance while at BGB. If a clinic accepts them, they start on methadone maintenance while they are still residents here. It could significantly affect the lives of our patients if we could provide a similar service in helping them to transition to Suboxone maintenance therapy when they leave BGB.

Acknowledgment

The authors would like to thank Joy Neary, RN, for her insight and input.

References

1. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: Extrapolating from the laboratory to the clinic. Drug Alcohol Depend 2003; 70:S13.
2. Johnson RE, Strain EC Amass L. Buprenorphine: How to use it right. Drug Alcohol Depend 2003; 70:S63.
3. Reckitt Benckiser Pharmaceuticals, Inc. Dosing guidance for Suboxone and Subutex in short- and long-term medical withdrawal. 2003.

Sidebar

Patience pays off

A 29-year-old mother of two addicted to Vicodin came to BGB for treatment. On admission she stated that she had been taking approximately 40 pills a day for the past year. She was detoxed during this admission with a seven-day methadone taper and left BGB in good spirits after 23 days.

She returned five months later. At intake on this second visit she stated that she had been able to maintain abstinence for three months but then relapsed, and for the past two months had again been taking 40 Vicodin tabs a day. We explained that this time we would be using Subutex for her detox; she was amenable to this.

Once into her detox, however, she voiced considerable complaint. On day three she told us that she was very unhappy with the Subutex, that it wasn't working at all, and that she wanted to be switched to methadone. We encouraged her to be patient, to use the opiate protocol meds, and to drink plenty of water. Her attitude improved on subsequent days, and when she completed her detox with Subutex we met with her privately and asked her to compare her two detox treatments. She said she was unhappy with Subutex at first because she did not feel “high” like she had while taking methadone, and for that reason she thought it wasn't working. But she admitted that Subutex had resolved just about all of her withdrawal symptoms from the beginning, and she stated that she had felt “normal” while taking the medication. When asked which medication she would choose if she ever had to undergo another detox, she quickly and emphatically said Subutex.