Very minute amounts of naloxone do get absorbed in some patients. Every time it has been studied the amount of absorption is far too insufficient to cause any clinical effects. Also, for some unknown reason bioavailability of buprenorphine is higher in the combination product than in the mono buprenorphine. Buprenorphine and naloxone have about the same affinity for the mu-opioid receptor. Even if some naloxone is absorbed, buprenorphine is at least partially preventing it from having any action at the mu-opioid receptor. The bottom line is that physicians do not ever need to worry about naloxone absorption when prescribing buprenorphine/naloxone and should strive to use this formulation in all but pregnant patients.
Andrew Saxon, MD
The clinical question reflects a common challenge during the induction and early stabilization phase in which patients start buprenorphine/naloxone treatment without precipitated withdrawal but then report unremitting or new nausea, vomiting, or headache. There are 2 main considerations that come to mind in such scenarios: 1) is this persistent or prolonged withdrawal in which opioid replacement with buprenorphine is inadequate, or 2) is this is a buprenorphine medication side effect?
The incidence of persistent withdrawal lasting more than a couple days after buprenorphine initiation has not been routinely assessed in most treatment trials. However, a primary care study found about 5% of patients experienced prolonged withdrawal symptoms and the risk may be higher in methadone transfers (Lee et al JGIM 2008). In the current case, there may be some ambiguity as to what constitutes withdrawal or a side effect, given that the potential side effects (e.g., nausea, vomiting, headache) overlap with potential withdrawal symptoms.
In such situations, serial assessments of withdrawal during the induction and early stabilization phase of treatment are very useful. Three examples of standardized scales include: the Clinical Opioid Withdrawal Scale (COWS), Objective Opioid Withdrawal Scale (OOWS), and Subjective Opioid Withdrawal Scale (SOWS), all of which help provide a more granular look at the constellation of withdrawal symptoms and also allow tracking of change over time. In the case being considered, I would prefer the SOWS, as there are more items (16 total) and they all inquire about withdrawal from the patient’s perspective (Handelsman et al Am J Drug Alc Abuse, 1987). There probably won’t be much objective indication of withdrawal a week after mediation initiation (e.g., autonomic hyperactivity, diaphoresis, pupil dilation, etc.), which limits the utility of the COWS or OOWS for the current clinical case. If opioid replacement is inadequate and buprenorphine dosing is too low, you would expect to see signs and symptoms indicating protracted withdrawal, such as anxiety, restlessness, cravings, or sleep disturbance. Anecdotally, the GI aspects of the opioid withdrawal syndrome (abdominal cramps, nausea, vomiting) tend to be relieved relatively quickly after buprenorphine initiation. Based on this and the way dosing and symptoms progressed for the case over a week or two, the presence of an medication side-effect seems more likely.
Nausea, vomiting, and headache are common adverse effects of buprenorphine/naloxone treatment. The package insert for Suboxone film, which the patient received, reports rates of 15% for nausea, 8% for vomiting, and 36% for headache (http://www.suboxone.com/content/pdfs/prescribing-information.pdf; Revised April 2014). Although the insert doesn’t provide a citation, I suspect these numbers came from the Fudala et al, NEJM, 2003 study, which tested the buprenorphine/naloxone tablet compared to buprenorphine mono product tablet and placebo over a 4 week period.
There are several strategies to manage side-effects of buprenorphine/naloxone:
1) A gradual dose reduction while carefully monitoring and balancing against emergent withdrawal and relapse risk
2) Split dosing – this can be done beyond BID to TID or even QID to minimize the side-effects related to rapid increases in medication blood levels. In this situation I encourage patients to dose with a fixed interval at specific time points to avoid dosing based on internal or external cues as the latter may perpetuate the preoccupation with the medication-taking and frequent self-monitoring of distress.
3) Adjunctive medication to target the side-effects
4) Transition to another buprenorphine/naloxone product (there are 4 available, including Suboxone film, generic tablets, Zubsolv tablets, or Bunavail buccal film) or to buprenorphine mono product. Interestingly, the Fudala 2003 study did not find a significant difference between combination bup/nx tablet and buprenorphine mono product adverse event rates, though sample size may have been a limitation.
5) Continue treatment as is: anecdotally some adverse effects early in treatment seem to extinguish over time, in particular if they are mild, and reassurance plus time may suffice for resolution.
6) Allergy consideration: Lastly, an allergic reaction was posited in the case. Although the constellation of symptoms seems an unlikely presentation of a mast cell-mediated allergy, the risks/benefits assessment for stopping vs continuing treatment with a buprenorphine product needs to be individually weighed. In case when the risks outweigh benefits, a transition to one of the other medications approved for treatment of opioid use disorder (methadone or naltrexone) should be considered.
Erik Gunderson, MD
There is a clear dose-dependent effect of buprenorphine, with higher dose more effective, and plasma level usually correlates with the dose but there is a significant variability in clinical response and a significant heterogeneity of patients therefore it is very difficult to predict what plasma level may be “therapeutic” for which patients. There were many attempts to come up with the therapeutic level of methadone but there was so much variability that this was abandoned (methadone has no active metabolites unlike buprenorphine so it should have been easier). It may be worthwhile to start collecting buprenorphine plasma levels to correlate it with the dose and clinical response as a part of clinical research, but there is no data to support using plasma levels in making any clinical decisions. On the other hand, changing dose, dosing timing and dose frequency (factors affecting plasma levels) should certainly be explored to maximize clinical response.
Adam Bisaga, MD
There is no specific evidence-based treatment for these patients so it is a matter of trying various interventions and seeing what might work. I actually like your idea of switching to Bunavail which would be harder to inject if it is even possible to do so. Other options include transferring the patients to methadone maintenance if that is available, withdrawing them from buprenorphine and whatever other opioids they might be using and starting them on extended release naltrexone, or doing buprenorphine implants if they are available in your community (although the latter would be off-label use since these patients are not stable). It won’t help in the present or immediate future, but in the not too distant future it looks likely that a 30 day buprenorphine injection formulation will become available which should avoid concerns about misuse or diversion. Discharging the patients might be a last resort because they are likely to do even worse when totally out of treatment, but it is also important to take care of yourself first. You are dealing with some very challenging patients, and you are to be lauded for working so hard to save their lives in the face of these very virulent forms of opioid use disorder they are suffering from.
Andrew Saxon, MD
It is not legal for a physician without a DEA X-number to prescribe buprenorphine for the treatment of opioid use disorder even in a covering capacity. The ideal plan in this situation would be to have some of the covering providers take the eight-hour training and get their X-numbers at least for coverage purposes even if they do not intend to have their own panel of buprenorphine patients. A somewhat less ideal alternative is to have the physician with the X-number make sure that a sufficient prescriptions have been written in advance to cover all her/his patients during the time she/he is away. A final alternative would be to get physicians from outside the health system who do have X-numbers to provide the urgent coverage when needed.
Andrew Saxon, MD
Most physicians choose not to dispense from their practice because of the extra paper work and locking cabinets involved, but it is certainly fine to do so if you are willing to complete the dispensing logs and keep the medication secure. I am not aware of any pharmacies delivering to the office, and unless the medication was intended for a specific patient who was there to receive it from the pharmacy, you would essentially then be storing and dispensing it and would still need to keep records. Again, each practice setting is different, but I think the most common way to handle the initial prescription for induction is to give the patient a prescription for the amount of medication expected to be necessary until the next visit, usually enough for a total of 8 mg (or its equivalent if using Zubsolv or Bunavail) on day 1 and up to 16 mg on subsequent induction days. If you are doing in-office induction, ask the patient to return to the office with the prescription before taking any medication. You can then observe the patient taking medication from the prescription. If doing home induction, then obviously the patient takes the prescription home and follows the instructions you have provided for how to start the medication. If the patient absconds with the prescription (I have never had it happen) and never returns, the patient has a most a week’s supply of medication. You have just performed a clear assessment that this patient is not appropriate for office-based opioid treatment, and you would probably choose not to continue to treat this patient in your practice.
Andrew Saxon, MD
Many patients do seem to prefer to take buprenorphine/naloxone in divided doses despite the fact that multiple doses per day are not necessary from a purely pharmacological perspective when only treating opioid use disorder. For patients who have both chronic pain and opioid use disorder divided doses may be appropriate since the duration of analgesic effect of buprenorphine appears to be shorter than the duration of effect in eliminating opioid withdrawal symptoms. Since we really cannot control how our patients take the medication, my own approach is to educate the patients about the benefits of once daily dosing, but if the patients prefer to use divided doses for psychological reasons, I accept that. From everything I have been able to glean from looking at studies of naloxone absorption, such absorption is insufficient to cause clinical effects. Thus, the idea that naloxone absorption is causing aversive experiences is a myth, and does not represent an explanation for the desire for divided doses.
Andrew Saxon, MD
This looks like a simple question that should have a simple answer but unfortunately this is not a case. Unlike with converting full agonists (e.g., morphine to methadone to hydromorphone) there is no easy way to to find a dose equivalency for morphine to buprenorphine because buprenorphine has a very different pharmacology. Depending on the situation such as: 1) the state of the organism (level of pain and level of physical dependence and tolerance) and 2) the effect you are looking at (pain, respiration, euphoria) buprenorphine may act as a partial agonist or a full agonist and the potency (dose equivalency) will differ depending on the dose range (the ratio will not be the same for bup 0.5 mg vs 30 mg). To complicate it further buprenorphine acts at other receptors producing analgesic and psychoactive effects. And to complicate it even more, to transition someone from morphine to buprenorphine patient will need to experience withdrawal and depending of how much withdrawal they go through they may require different dose of buprenorphine to stabilize afterwards.
Because it is so complex you will find conversion rations anywhere from 1:3 to even 1:60 which basically mean that those conversions are not very useful.
In practice, you should have an individual approach in every situation, slowly titrating buprenorphine to the desired effect (eg pain relief). Luckily buprenorphine is relatively safe so that therapeutic index is rather large.
Adam Bisaga, MD
What do you then document in your progress notes ?
Here is a useful webinar describing DEA requirements.DEA record keeping requirements for buprenorphine treatment are quite involved which is why most OBOT practices do not dispense medications (store them onsite). First of all I would like to reassure you that DEA should not be reading your confidential clinical notes. DEA agents should only be concerned with the documentation of the number of active patients being prescribed buprenorphine, and the record of all prescriptions given. If however you decide to dispense medication on site then:
The most detailed guidelines were developed by SAMHSA and published in 2004 as a part of their Treatment Improvement Protocol series (TIP 40) titled: ”Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction.” I like to refer to a version of guidelines titled “Opioid Addiction Treatment in the Medical Office” was adopted as a policy by the House of Delegates of the Federation of State Medical Boards of the United States. Here is what these guidelines recommend to be included in the medical record:As far as the content of clinical documentation there are guidelines proposed by the various federal and state agencies that cover this topic.
The prescribing physician should keep accurate and complete records to include (1) the medical history and physical examination; (2) diagnostic, therapeutic and laboratory results; (3) evaluations and consultations; (4) treatment objectives; (5) discussion of risks and benefits; (6) treatments; (7) medications (including date, type, dosage, and quantity prescribed and/or dispensed to each patient); (8) a physical inventory of all Schedules III, IV, and V controlled substances on hand that are dispensed by the physician in the course of maintenance or detoxification treatment of an individual; (9) instructions and agreements; and (10) periodic reviews. Records should remain current and be maintained in an accessible manner and readily available for review. The physician must adhere to the special confidentiality requirements of 42CFR, Part 2, which apply to the treatment of drug and alcohol addiction, including the prohibition against release of records or other information, except pursuant to a proper patient consent or court order in full compliance with 42CFR2, or the Federal or State officials listed in 42CFR2, or in cases of true medical emergency or for the mandatory reporting of child abuse.
Below is a detailed description of what may be included in each of the sections of the Medical Record. Again this is only a guideline, which does not have to be followed exactly but I find it very useful as it can be very helpful in delivering and documenting excellent care.
Evaluation of the patient
A recent, complete medical history and physical examination must be documented in the medical record. The medical record should document the nature of the patient’s addiction(s), evaluate underlying or coexisting diseases or conditions, the effect on physical and psychological function, and history of substance abuse and any treatments therefore. The medical record should also document the suitability of the patient for office-based treatment based upon recognized diagnostic criteria. Diagnosis of OUD should be documented.
The written treatment plan should state objectives that will be used to determine treatment success, such as freedom from intoxication, improved physical function, psychosocial function and compliance and should indicate if any further diagnostic evaluations are planned, as well as counseling, psychiatric management or other ancillary services. This plan should be reviewed periodically. After treatment begins, the physician should adjust drug therapy to the individual medical needs of each patient. Treatment goals, other treatment modalities or a rehabilitation program should be evaluated and discussed with the patient. The treatment plan should also contain contingencies for treatment failure (i.e., due to failure to comply with the treatment plan, abuse of other opioids, or evidence that the Schedules III–V medications are not being taken).
Informed Consent and Agreement for Treatment
with the patient and, with appropriate consent of the patient, significant other(s), family members, or guardian. The patient should receive opioids from only one physician and/or one pharmacy when possible. The physician should employ the use of a written agreement between physician and patient addressing such issues as (1) alternative treatment options; (2) regular toxicologic testing for drugs of abuse and therapeutic drug levels (if available and indicated); (3) number and frequency of all prescription refills and (4) reasons for which drug therapy may be discontinued (i.e., violation of agreement). The physician should discuss the risks and benefits of the use of buprenorphine
Periodic Patient Evaluation
Patients should be seen at reasonable intervals (at least weekly during initial treatment) based upon the individual circumstance of the patient. Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of treatment plan, and to assess how the patient is handling the prescribed medication. Once a stable dosage is achieved and urine (or other toxicologic) tests are free of illicit drugs, less frequent office visits may be initiated (monthly may be reasonable for patients on a stable dose of the prescribed medication(s) who are making progress toward treatment objectives). Continuation or modification of opioid therapy should depend on the physician’s evaluation of progress toward stated treatment objectives such as (1) absence of toxicity; (2) absence of medical or behavioral adverse effects; (3) responsible handling of medications; (4) compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy and/or other psychosocial modalities); and (5) abstinence from illicit drug use. If reasonable treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continued treatment.
The physician should refer the patient as necessary for additional evaluation and treatment in order to achieve treatment objectives. The physician should pursue a team approach to the treatment of opioid addiction, including referral for counseling and other ancillary services. Ongoing communication between the physician and consultants is necessary to ensure appropriate compliance with the treatment plan. This may be included in the formal treatment agreement between the physician and patient. Special attention should be given to those patients who are at risk for misusing their medications and those whose living or work arrangements pose a risk for medication misuse or diversion. The management of addiction in patients with comorbid psychiatric disorders requires extra care, monitoring, documentation and consultation with or referral to a mental health professional.
Adam Bisaga, MD
There is new evidence showing that buprenorphine doses above 16 mg/d may be more effective than lower doses (Hser et al., 2013). In this study, patients treated with doses higher than 16 mg had 40% lower odds of dropout as compared to patients treated with doses lower than 16 mg/d and there appeared to be a monotonic relationship between the dosage and outcome.
In my personal (office-based) experience less than 25% of patients (e.g., individuals who were using large amounts of i.v. heroin of prescription opioids) need doses greater than 16 mg and most of the time this occurs early in treatment. Some of those patients can over time stabilize on doses below 16 mg/d while others continue to struggle (report cravings and continue using) even if the dose is increased above 24 mg. Therefore it is not clear if this is an issue of the insufficient dose or the ceiling on effectiveness. In patients who continue using illicit opioids while compliant with high doses of buprenorphine I recommend that they try methadone, which has greater effectiveness than buprenorphine in suppressing opioid use at higher doses. However, most often patients who do not respond to high buprenorphine doses are not fully compliant with the medication and in those cases supervised dosing would be the first intervention.
Adam Bisaga, MD
When completing the waiver form to get the buprenorphine waiver from CSAT and the X-number from DEA, you will find that question number 11 asks if you will consent to having your name released to the physician locator website. Simply check no, that you do not consent, and you will not be listed. If for some reason you are already listed and want to be removed, follow the directions below copied from the SAMHSA website:
I am a waived physician and would like to add, change, or remove my listing on the SAMHSA Buprenorphine Physician Locator Web site. How do I do this?
Waived physicians may call 1-866-BUP-CSAT (1-866-287-2728) or e-mail firstname.lastname@example.org with requests to change Locator listings. There is also a new on-line form for physicians to request changes to their contact information. Click on Update Physician Contact Information and use the State Medical License Number and DEA Registration Number that we currently have on file to locate and change your information.
Andrew Saxon, MD
12 mg per of buprenorphine is a sub-therapeutic dose for many patients, especially early in treatment. The appropriate response to a patient who continues using illicit opioids while on buprenorphine is to raise the buprenorphine dose, which, unfortunately, this patient refuses to do. If a sufficient number of mu-opioid receptors are not occupied by buprenorphine, which is certainly possible here, the patient may feel some of the effects of IV heroin. It is likely that this patient wants to be maintained on a dose high enough to avoid serious withdrawal symptoms so that he doesn’t have to be seeking illicit opioids on a daily basis, but low enough that he can experience some euphoria when using heroin.
In this situation there are three choices: 1) Refer patient to an opioid treatment program where dose of buprenorphine can be raised to therapeutic level and administered all at once under observation or he can be transitioned to methadone there; 2) Continue working with the patient with a goal of cessation of use over time or agreement to the dose increase, while accepting the fact that the patient may remain unstable for some time; and 3) Discharge the patient from care since patient is non-compliant with treatment recommendation to increase the dose.
Andrew Saxon, MD
The question of duration of opioid agonist therapy treatment, in the treatment of opioid addiction, has been debated and discussed for the entire 50 year modern day experience with this treatment modality. It is among, if not the most fundamental, issue in opioid agonist therapy. This question started to be raised in 1965 when the initial successful outcome studies with methadone maintenance were published by Dole, Nyswander and Kreek. These researchers and clinicians felt that opioid addiction represented a neurobiological deficiency, and that occupancy of the mu receptor by a long acting opioid, such as methadone would normalize and stabilize the patient’s “brain.” This normalization would then lead to returning to work, school, family, and other rewarding and productive activities. The mechanism of action of buprenorphine, a long acting partial mu agonist would be similar to the methadone MOA “concept.”
With that as background, I think that the literature over the past 50 years, generally supports the following: 1. Relapse to opioid addiction is common in patients who discontinue opioid agonist therapy. 2. “Detox” regimens, of any duration, do not prevent relapse for most patients. 3. Patients who remain on opioid agonist therapy, properly monitored, have better life outcomes than those who discontinue. 4. There are relatively few long term serious adverse effects from either methadone or buprenorphine. 5. No study has established the optimal duration of opioid agonist therapy.
So, some patients will do better with indefinite life long therapy on buprenorphine, and others may wish to taper after a certain amount of time. Tapering should be closely monitored, and re-institution of buprenorphine should be available. Psychosocial treatments, always important, are particularly important during the tapering and discontinuing phase of opioid agonist therapy. A peculiarity in opioid agonist therapy is the concept that those who are doing well should think about discontinuing. We don’t follow this paradigm in other chronic disease treatments. Some patients may not want or need long term opioid agonist therapy, some may transition to naltrexone, some may require methadone, and some may decide that they feel and function at their maximal capacity, at home and at work, while on opioid agonist therapy, and therefore desire to continue treatment indefinitely.
Both patients, and particularly significant others, should be disabused of the idea, that the goal of starting opioid agonist therapy is to see how fast you can get “off of it.” This requires an opioid addiction 101, and an opioid agonist therapy 101 discussion with both the patient and significant others.
So, to answer the question directly, evidence on the duration of buprenorphine treatment that accumulated over the past decade suggests that the treatment of each patient should be individualized, without any arbitrary treatment duration limits, which is what we do in every other area of medicine.
Edwin Salsitz, MD
It sounds like the scenario being described relates to methadone when used for treatment of opioid addiction, not for treatment of pain. The latter is not subject to the same rules as the former.
Methadone used for the treatment of opioid addiction requires adherence with a number of federal and state regulations and rules. At the federal level, these include regulations promulgated by the Center for Substance Abuse Treatment (CSAT) within SAMHSA and DEA regulations (http://www.deadiversion.usdoj.gov/21cfr/cfr/index.html). OTPs also need to meet accreditation standards as set by whatever accreditation organization the OTP chooses to use (CARF, Joint Commission). Then there are a number of state specific regulations.
I would recommend going to the SAMHSA/CSAT website for more information as the details of the specifications and regulations are too many to quickly detail here. http://www.samhsa.gov/medication-assisted-treatment
Another good resource is the recently updated CSAT guideline that interprets the regulations. http://store.samhsa.gov/shin/content/PEP15-FEDGUIDEOTP/PEP15-FEDGUIDEOTP.pdf
One universally applicable regulation is that methadone in OTPs is not prescribed, it’s ordered, and physicians do not need a DATA 2000 waiver in order to practice in an OTP.
As for prescribing methadone in an ER, the DEA regs state that for patients who present with an opioid addiction NOT already in treatment with an OTP, the physician “may administer opioids to a patient for the purpose of relieving acute withdrawal symptoms while arrangements are made to refer the patient for addiction treatment, under the following conditions [21 CFR 1306.07(b)]: • Not more than one day’s medication may be administered or given to your patient at one time, • This treatment may not be carried out for more than three days, and • This three-day period cannot be renewed or extended.”
If the patient is already enrolled in an OTP, then “A physician, or authorized hospital staff, may administer or dispense narcotic drugs in a hospital to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction. [21 CFR 1306.07(c)].”
In terms of reimbursement and billing and which codes to use, these are difficult to answer as it depends on the insurer and the state. Each state’s Medicaid systems on this are different so I would advise seeking information from your state Medicaid office, or your state’s ASAM or AATOD chapter, if you have these. Commercial insurers also vary, and Medicare at this point does not reimburse for OTP services. That may be changing. There is more information on this also available on the AATOD website at http://www.aatod.org/Yngvild Olsen, MD
Methadone may prolong the QTc interval. Generally, this QTc prolongation is dose related, and also multifactorial. Dosages above 100-120mg, are more commonly associated with QTc prolongation than lower doses. There is controversy in OTPs, on whether routine baseline EKGs, and follow-up EKGs when maintenance dosages are achieved, and again if the methadone dosage increases, should be performed. There were 2 Consensus Statements on this issue, one of which recommended such screening, and the other, which stated that there was not enough evidence to warrant EKG screening, and any delay in treatment would result in more morbidity and mortality secondary to ongoing opioid use disorder.
In terms of multifactorial etiology of a prolonged QTc in a methadone maintained patient the following should be assessed: 1. Magnesium and Potassium levels; low levels prolong the QTc 2. Concurrent use of other medications which prolong the QTc interval 3. Concurrent medications which inhibit CYP 3A4, 2D6, or 2B6. Serum methadone levels will be increased under this circumstance. 4. Use of cocaine, which may also prolong the QTc interval.
The upper limit of normal QTc is 450msec in men and 470mg in women. Prolongation of the QTc is of concern because it may lead to the development of Torsades d’Pointe, a ventricular arrhythmia, which may lead to syncope and sudden cardiac death. The threshold QTc interval for Torsades is generally considered to be 500msec.
Therefore, if the QTc interval is below 500msec, and the other factors are not present, the dose of methadone may be increased. Of note is that buprenorphine does not prolong the QTc interval in a clinically meaningful manner. In some cases switching from methadone to buprenorphine is a clinical option for a persistent QTc prolongation on methadone. If higher doses of methadone must be maintained, and the QTc is prolonged above 500msec, a cardiology consult should be obtained. An implantable intra-cardiac defibrillator may be clinically indicated.Ed Salsitz, MD
This is a commonly encountered clinical scenario where a patient treated with buprenorphine may have other psychiatric problems that may be require medications that are also controlled substances (benzodiazepines or psychostimulants). In these case a higher level of monitoring is required as the risk for medication misuse or adverse effect is higher.
Before taking on the patient you may want to contact the other prescriber to better understand indication, therapeutic response, treatment compliance, and any problems related to treatment and of course both providers should agree with the plan of treating the patient with these medications. In optimal situation all controlled substances are prescribed by the same provider to assure close monitoring and safe prescribing but if that is not possible than a plan for ongoing communication needs to be established. Keeping visits more frequent and giving smaller supplies of medications is a good idea especially at the beginning of treatment when you are getting to know the patient. During the visits you want to make sure that you discuss the issue of diversion/misuse and you may consider a consent form to document a thorough discussion of the treatment framework/patient responsibilities and the plan for monitoring.
You want to implement reliable toxicology monitoring and pill counts, and monitor for any behaviors suggesting of possible misuse of medications, both buprenorphine and benzodiazepines (such as demands for specific preparations, discordant pill count/lost scripts, dose escalation, symptoms of intoxication/withdrawal). When prescribing other controlled substances make sure that long-acting agents (lower abuse liability) are prescribed, medications are to be taken regularly and not prn. With all that strict treatment structure you will have a chance to see if prescribing is appropriate/safe and when you have this reassurance you may want to decrease the frequency of visits to monthly as patient is stable and continues to improve. Working with such patients requires a bit more experience treating substance use disorder so I recommend that you connect with the PCSS mentor that could be help you as you are becoming more experienced with this population.
Adam Bisaga, MD
The prescribing physician (or the delegated others; advance practice nurse or PA) must assure that patients receiving unsupervised dosing are adequately stable to manage it safely without high risk of diversion. As far as the latter goes, in addition to limiting takehomes to patients at particular risk of diversion, the program should have a comprehensive diversion control plan. The criteria listed in 42CFR8 must be considered whenever deciding whether a particular patient can earn (or whether they should retain) takehomes. The questions don’t need to be considered criteria which all need to be met for every patient for each take-home, but they must be considered. In the end, the risks must be outweighed by the potential therapeutic benefit of providing the take-home.
As far as the example given, since dosing is available on all days of the week, only patients considered appropriate by the program physician should receive unsupervised doses. The remainder should be dosed on-site on Sundays. That said, many programs routinely give all their patients takehomes on Sunday, as those programs are closed that day of the week. This is considered by many to be of relatively low risk. For patients who are considered at particular risk (for example, a patient with traumatic brain injury and proclivity for forgetting they already took their day’s dose), alternate arrangements should be made so he can get dosed at a program open that day. The fact is that in most programs, this occurs extremely rarely – especially in relation to holiday dosing. Even most 7d/wk programs provide take-home doses to all patients on major holidays, or in anticipation of a major weather event that would make travel unsafe.
The alternatives that I see as viable include: 1) Continue to limit supervised takehomes to any patient who he feels cannot safely manage it, 2) Increase resources to keep program open on Sundays and holiday, and 3) Reach out to another area program that is open on Sundays to arrange for regular guest dosing for those patients who are not felt safe for unsupervised dosing, but cannot be serviced at the home program.
Please note that national accreditation bodies and other regulatory oversight agencies stress importance of patient-centered care and require a range of days and hours that are consistent with the vast majority of patients served. Putting the patient at risk of opioid withdrawal also puts the unstable patient in a position where they are very likely to use illicit opioids, and therefore be at high risk of overdose.
Finally, another option for some patients may be to provide buprenorphine rather than methadone maintenance, when this is considered clinically viable for the particular patient. This can eliminate the problem of unsupervised dosing in two ways – 1) the risk of overdose if the patient double-doses using his/her take-home is much lower with buprenorphine vs. methadone. (of course, the medication could still be diverted – but diverted buprenorphine is less dangerous than diverted methadone), and 2) research studies have demonstrated that buprenorphine can be given every 2 days (double dose), or even every 3 days (triple dose) without significant signs/symptoms of withdrawal. Therefore, double buprenorphine dose can be given on Saturdays, carrying the patient through until Monday.
Ken Stoller, MD
Like many clinical questions, the answer is “it depends.” In brief, it is recommended that you have a reference lab available to confirm some in-office toxicology findings, but not all findings need confirmation. Generally I obtain confirmation where the patient denies use, especially if I plan to act on the findings (e.g. increasing structure such as requiring more frequent visits, intensifying psychosocial treatment, or, tapering/discontinuing agonist treatment). Assuming you are not providing forensic evaluations (e.g. for probation/parole or DCF), chain of custody is not needed, but in some circumstances you might want to obtain observed specimens, especially if you suspect tampering.Peter Friedmann, MD Providence VA Medical Center
Several issues can be raised in response to the question about buprenorphine-prescribing physician writing a letter in support of the patient’s application for a commercial driving license (CDL). Generally states and cities follow regulations, which vary in their laws and rules about driving when on opioid agonist therapy, so the decision will be taken by the relevant board regardless of the physician’s clinical “recommendation.” The physician can offer to write an advocacy letter in support of the patient, documenting the details of the treatment, hopefully a history of negative urine toxicologies, and details of the patient’s functional status. Of course, the patient would have to consent to the disclosure. However a physician should NOT write a letter of support of CDL without disclosing in the letter that the patient is on buprenorphine maintenance. This is unethical and can have negative legal implications if it comes up in court.
In New York City, I have had a positive experience. Our electrical utility, ConEd, our transportation authority, MTA, and our sanitation department, all allow stable patients on methadone or buprenorphine to drive vehicles, and engage in other safety sensitive positions. The employers require random UDTs, and an annual letter from me documenting clinical stability.
If your jurisdiction does not allow these exceptions, one option is to consider transferring the patient to naltrexone. Patients in this type of employment situation, are listed as good potential candidates for naltrexone therapy.
The other issue is whether patients on stable maintenance or buprenorphine doses, who are in recovery/remission, are impaired when operating a motor vehicle. The consensus is that they are NOT, as long as the aforementioned provisos are present.
Here is an excerpt from a California ruling on the issue as it relates to methadone maintenance:
“Methadone maintenance treatment programs are putting many heroin addicts on the road to a normal life. A driver’s license is often a basic part of rehabilitation because it enables participants in these programs to drive and hold regular jobs. It is necessary that this act go into effect immediately in order to avoid the disastrous effects upon rehabilitation due to an inability to drive to work.
Cal. Stats. 1971, ch. 363, § 5, 730, cited in People v. Gonzales, 2003 Cal. App. Unpub. LEXIS 6596, 28 (2003)
In Conclusion, the driving of an individual participating in long-term methadone maintenance is not, under ordinary circumstances, impaired to an appreciable degree by their ingestion of methadone. For this reason, an individual who drives after taking prescribed methadone is not per se driving under the influence of methadone, and there is no caselaw suggesting that being involved in a traffic accident changes that legal status. The California Vehicle Code’s explicit willingness to allow methadone therapy participants to drive further supports the conclusion that such activity is not a per se violation of § 23152.
So, the physician should advocate for the patient to obtain CDL, but cannot “hide” the fact of buprenorphine treatment. The local rules and regulations should be checked, and if there is no other option, antagonist therapy should be considered.
Edwin Salsitz, MD with assistance from Richard Soper, MD and Mark Kraus, MD Cal. Stats. 1971, ch. 363, § 5, 730, cited in People v. Gonzales, 2003 Cal. App. Unpub. LEXIS 6596, 28 (2003) (emphasis added).
Drug toxicology testing is a necessary component of addiction treatment. Drug testing provides an objective measure to guide many facets of treatment. Urine is the most common matrix but other matrices, such as saliva are also useful.
The term random, when used in reference to UDT (urine drug testing), can have 2 operational meanings:
In my own practice I do not routinely use option number 2 without having some indication that the patient is not adhering to the treatment plan and making progress toward the treatment goals. The PDMP, significant others, behavior at visits, and functional issues such as employment, family involvement, or pursuing education can provide an indication about overall progress.
I am concerned that routinely calling patients to come in unexpectedly may send the message that you do not trust the patient, which may interfere with the patient provider relationship. We don’t want to be perceived as always assuming the patient might be guilty rather than the presumption of innocence. In addition if patients are employed this may jeopardize their jobs and also send a negative signal to significant others.
In the case of urine drug testing for buprenorphine, you will have to consider using GC/LC/MS confirmatory testing in some cases. The screening immunoassay will test only for the parent compound–buprenorphine. To be sure the patient is taking the buprenorphine, it is necessary to do testing for buprenorphine metabolites since a patient can “spike” a urine by putting buprenorphine into the specimen.
There is a place for random unscheduled drug testing and on occasion for an “observed” urine collection. I don’t have a solution to the voicemail problem. Some patients might be better served in an OTP, with daily observed dosing until more stability is achieved.
Edwin Salsitz, MD
Quantitative urine testing can be an important method for both recognizing buprenorphine misuse and demonstrating treatment adherence. Typically conducted with GC/MS, quantitative testing provides confirmation of medication in the urine, and also allows recognition of the metabolite norbuprenorphine. Such monitoring is an important adjunct to the commonly used point-of-service urine dip tests.
From the PCSS Guidance on Adherence monitoring originally written by Judy Martin, MD and updated by Maria Sullivan, MD (http://pcssmat.wpengine.com/wp-content/uploads/2014/02/PCSS-MATGuidanceAdherence-diversion-bup.Martin.pdf): “Dipsticks or laboratory-based tests for buprenorphine in the urine are inexpensive and can be part of routine office-based monitoring. The presence of buprenorphine in the urine indicates that the patient has taken some portion of the prescribed dose. Absence of buprenorphine in the urine supports non-adherence. Testing for buprenorphine metabolites (only present if buprenorphine is metabolized) may be included to minimize the possibility that buprenorphine is added directly to the urine sample.”
The above clinical scenario is complicated as there are high levels of buprenorphine and naloxone, raising concern about tampering, yet the sample also contained norbuprenophine, indicating that some metabolism had taken place and that the urine came from a person who had ingested a buprenophine-containing product.
The PCSS Guidance provides some recommendations on potential procedural strategies to consider when conducting urine toxicology testing: “Of course, urine tests can be subverted or replaced unless the collection is also observed. Common strategies to minimize falsified urine collections are to: disallow carry-in items (purses, backpacks) into the bathroom, turning-off running water and coloring toilet water to eliminate possibility of dilution, monitoring the bathroom door so that only one person can go in, and testing the temperature of the urine immediately after voiding.”
Although these approaches may be useful (e.g., we incorporate temperature confirmation with test strips on the cup), others may not be feasible in some settings (e.g., coloring toilet/sink water, testing with direct observation). Furthermore, as it relates to the above case scenario, none of the above-mentioned approaches besides direct observation can prevent a patient from adding a buprenorphine/naloxone-containing product directly to his or her urine.
I concur that the high levels of buprenorphine and naloxone coupled with low levels of norbuprenophine raise concern that the patient added buprenorphine/naloxone directly to the urine sample (McMillin GA, J Anal Toxicol 2012). Unfortunately, most studies examining quantitative testing are in the toxicology literature and often focus on reporting the testing methodology rather than generating data specifically for clinical assessment and decision-making. Although there remains a need for more clinical research on how to interpret quantitative urine testing during buprenorphine treatment of opioid use disorder, the toxicology literature can help interpret the findings.
In general there seems to be a 2:1 – 3:1 ratio of norbuprenophine:buprenorphine in the urine, which in part might relate to the longer half-life of norbuprenorphine. A higher ratio of norbup:bup theoretically could theoretically indicate running out of medication early as the norbuprenorphine stays in the system a little longer.
In one particular study that examined buprenorphine, norbuprenorphine, and naloxone in urine (Tzatzarakis MN et al., J Anal Toxic 2015), the authors found a 2.5 ratio of norbup/bup and 0.3 ratio of naloxone/bup in the urine (mean daily bupreorphine dose wasn’t given but 16mg/d was “most common). Hence, the ratios of the clinical case (0.02 norbup/bup and ~2.95 for nal/bup) are off by an order of magnitude or more and seem consistent with tampering.
Furthermore, the Tzatzarakis study provides some other interesting findings on testing: Approximately 85% of samples tested positive for naloxone, 96% for norbup, and 94% for bup. It’s interesting that not all samples were positive, indicating the possibility for false negatives. Perhaps this relates to daily dose (the range in the study was 2 – 18 mg/d). Although the correlation between daily dose and urine concentration was “weak,” total dose administered in the past 12 months was strongly correlated. Hence, we should be cautious in interpreting negative findings, particularly in patients on low daily doses who are early in treatment.
I hope that the details regarding these specific data are useful rather than cumbersome. Challenges in interpreting urine drug testing remain, and there are numerous relevant questions, such as whether we should look: 1) solely at presence or absence of medication or metabolite, 2) concentration thresholds, and/or 3) concentration ratios. In examining medication levels, how do these relate to the patient’s average daily dose and length of time in treatment? What is the impact of dilution and should concentrations be creatinine-adjusted? How does dosing timing prior to urine collection influence the findings? Naloxone has such a short half life and doesn’t stay in the system as long, so it’s unclear how this will impact its utility as a marker of medication adherence.
Last, interpreting and acting upon GC/MS quantitative tests in clinical practice should incorporate numerous factors regarding other areas of adherence and function. Perhaps most importantly, they provide a platform for communication about medication dosing, adherence, and potential misuse.
Erik Gunderson, MD
A person >18 years old, is not considered a minor in the United States, and may consent to medical treatment, including addiction treatment, without parental consent or notification.
Persons less than 18 years old are generally considered minors, but there is a wide state by state variation as to the definition of a minor.
Below are three links that provide further information on this issue.
The first link lists every state’s rules on treating minors. As one example, Alabama considers anyone over the age of 14 to be able to consent to treatment.
The second link is to a TIPS (Treatment Improvement Protocol), dealing with adolescents and addiction treatment.
And lastly, a link to a manual offering guidance to health care providers who directly treat minors in Pennsylvania
And here is a useful paragraph taken from Pennsylvania’s regulations on treating addictive disorders in minors.
“Substance Abuse Treatment
A minor who “suffers from the use of a controlled or harmful substance” can consent to medical care and counseling related to the diagnosis or treatment of a substance abuse problem. The consent of the minor’s parents or legal guardians is not necessary to authorize medical care or counseling related to such diagnosis or treatment. There is no age limit for giving consent to substance abuse treatment under Pennsylvania law; therefore, a provider may treat a minor who has consented to treatment if the provider determines that the consent is knowing and voluntary.
With regard to parental notification, Pennsylvania law states that a physician, organization, or agency operating a substance abuse program which provides counseling to a minor may, but is not obligated to, inform the parents or legal guardian of the minor as to the substance abuse treatment given or needed. However, if the program is federally assisted, the program may only disclose such information to the minor’s parent or guardian with the minor-patient’s prior written consent; this includes situations when disclosure of information to the minor’s parent or guardian is needed to obtain financial reimbursement
The buprenorphine product insert states: “ Safety and effectiveness of buprenorphine sublingual film in patients below the age of 16 has not been established.”
There is also a PCSS-MAT Guidance on this topic:
Putting this all together: There is wide variation state by state on the regulations involved in treating minors for substance use disorders. The treating physician should inquire about his/her state regulations from the Department of Health, or the State Addiction Treatment Authority. Seeking consultation or directly coordinating care with a pediatrician or adolescent medicine specialist in your practice area would be advisable. Of course, it is always preferable, when possible, to have significant others involved in the care of adolescents. Significant others can provide help with the safe storage, and dispensing of buprenorphine to adolescents.
Edwin Salsitz, MD
There is no absolute answer to this, and every situation needs to be individually assessed. Political and cultural changes notwithstanding, the use of marijuana by a person who has and/or is being treated for another addiction is different than someone who is a so called recreational user without any other addictive disorder. Most of the progress I make with patients who problematically use marijuana requires the development of a therapeutic relationship over several visits. Thus I will not withhold Buprenorphine treatment, nor discontinue it soon after stabilization just because THC continues to show up in testing. I use a motivational interviewing approach and make use especially of pointing out Discrepancy in the goals the patient has and the behaviors that continue that run counter to those goals. I want to see the patient engaging in meaningful discussions regarding the marijuana use and not emphatically reject any attempt to discuss the marijuana use as it relates to the larger Recovery goals. I want to see reduction in use, significant less use in potentially harmful situations (eg. while caring for young children, at work, driving, etc.) and progress in all aspects of Recovery. Certainly I have a very low tolerance for any marijuana use if they continue to have slips with opiates, cocaine, benzos, etc. I may also insist on attending IOP programs as a condition of continuing Buprenorphine treatment. There are times when treating young adults where I will insist on a parent joining us in a treatment session when marijuana use continues to be an issue. If a Buprenorphine patient is arrogant, refuses to consider at least addressing the marijuana as a potential problem, etc. it may come to needing to discuss terminating my continuing to treat them.Michael Shore, MD
Everyone’s practice situation is a little bit unique, and each patient is a little unique so there is, of course, no absolutely firm answer to how often patients should be seen during the induction phase. The most common approaches would be either to see the patient within a few days of the first dose and then at one week after first dose or instead to have a phone visit within a few days and then see the patient in the office at the end of the first week. At that point weekly visits are usually reasonable for a few weeks to make sure the patient is stabilized. Then go to every 2 week or every 4 week visits. Since most patients come very close to full stability within the first week or two, for your practice situation, it would make sense to induct patients only during week 1 and early in week 2 of your 3 week cycle and not to induct anyone in the week prior to the time you will be off for a week. There is certainly no absolute contraindication for not inducting during that last week, but why create a potentially stressful situation for the patient or for yourself in the exceedingly rare event that the induction and stabilization does not go smoothly?Andrew Saxon, MD
Prior to initiating buprenorphine treatment, patients must first be seen by a waivered physician who signs off that the person is opioid dependent and appropriate for buprenorphine treatment and writes the orders. The nurse can manage the patient under the direction of the waivered provider following orders, protocols, and take verbal orders for dose adjustments, which will then need to be signed off.Kate Driscoll Malliarakis, PhD, ANP-BC, MAC Colleen LaBelle BSN RN-BC CARN Matt Tierney, NP, CNS
In an OTP, patients who are prescribed buprenorphine by a DATA-waivered PA or NP would be considered to be the NP’s or PA’s patients for purposes of the patient cap, not the OTP’s patients. This is because the authority for NPs and PAs to prescribe their patients buprenorphine is derived from their waivered status (which CARA authorized). Also OTP regs (42 CFR 8.12(h)(4)) state that, “Dosing and administration decisions shall be made by a program physician familiar with the most up-to-date product labeling.” Also, where required by state law, the NP/PA must provide treatment under the supervision of or in collaboration with a qualified physician.
A nurse or NP can “transmit” those MD orders to a pharmacy, but should choose language carefully to emphasize that they are “transmitting” an MD order and not mis-state that the NP or nurse is him- or herself giving a verbal order to the pharmacy. We are aware of the report that DEA inspectors made a clear point about this to an NP colleague in Oregon. The language used during the verbal order is critical on how it is presented. Lastly, all verbal orders must be followed up with a hard copy signed by the waivered provider.Kate Driscoll Malliarakis, PhD, ANP-BC, MAC Colleen LaBelle BSN RN-BC CARN Matt Tierney, NP, CNS
As an anesthesiologist, you might be able to sit for the American Board of Addiction Medicine (ABAM) Boards if you meet their eligibility criteria. This is a national certification and the 100 patient limit would still apply. Detailed information is available at www.abam.net. ABAM has established five (5) 2015 Eligibility Criteria that must be met by all physicians applying for the certification examination. They include having a valid medical license, completing medical school and residency (more details are on their site). You’d need 50 CME credits in the 2 year period prior to the board exam, 25 of which must be addiction related. Lastly, they require either completing an addiction fellowship or meeting their practice experience requirements below:
PRACTICE EXPERIENCE /OR COMPLETION OF AN ADDICTION MEDICINE FELLOWSHIP ACCREDITED BY THE ABAM FOUNDATION
Either Pathway A or Pathway B is required.
PATHWAY A – PRACTICE EXPERIENCE: ONE YEAR FULL-TIME EQUIVALENT (1,920 HOURS) OF WORK AS AN ATTENDING PHYSICIAN IN THE FIELD OF ADDICTION AND SUBSTANCE USE DISORDERS
– One (1) FTE is equal to a minimum of 1,920 hours of practice experience over the last 5 years
– Hours must be focused on the treatment of individuals with an addiction or substance use disorder, or the prevention of addiction or substance use disorders among individuals at risk. At least 400 hours must be clinical in nature. Exceptions to having 400 clinical hours will be considered on a case-by-case basis. For consideration of an exception, contact ABAMcertify@ABAM.net.
– Elective rotations during a residency are generally not permitted for use to fulfill this eligibility requirement. Addiction medicine FTE hours cannot be accrued until a primary residency is complete. Exceptions to this stipulation will be considered on a case-by-case basis. For consideration of an exception, contact ABAMcertify@ABAM.net.
PATHWAY B: COMPLETION OF AN ADDICTION MEDICINE FELLOWSHIP ACCREDITED BY THE ABAM FOUNDATION.
– A list of accredited fellowships can be found at http://abamfoundation.org/
– Candidates who have successfully completed an ABAM Foundation-accredited fellowship and are applying for the examination via this pathway are not required to meet or report the requirement for 50 CME credits in addiction medicine. The fellowship should be completed at least 2 weeks prior to the examination date. Exceptions to this requirement will be considered on a case-by-case basis. For consideration of an exception, contact ABAMcertify@ABAM.net.
In addition, ASAM has information on their site (www.asam.org, Home > Membership > Resident and Student Center > Paths to Certification) that may be of help, and I’ve included this paragraph for psychiatrists interested in certification:
“Addiction psychiatry is a subspecialty of psychiatry. Addiction psychiatry certification is bestowed by the American Board of Psychiatry and Neurology (ABPN), a member board of the American Board of Medical Specialties (ABMS). Psychiatrists interested in this subspecialty must complete a 1-year addiction psychiatry fellowship that has been accredited by the ACGME, meet the ABPN eligibility criteria and pass the ABPN certification examination.”
Erik Gunderson, MD