January 2009 EMN 7

InFocus

Buprenorphine: Toxicity and Overdose

This is one of the few reports of consequential overdose of buprenorphine in children. The retrospective review covers three years of data collected from poison centers for children under 6 with a history of BPN ingestion. There were 86 children who met the criteria, with a mean age of 2. The vast majority of ingestions occurred at the childs home, and all ingestions were considered unintentional and acute. The most commonly ingested was sublingual Suboxone, (BPN:naloxone in 4:1 ratio), either 2 mg or 8 mg, with a small number of Subutex (BPN only, no naloxone) tablets. Interestingly, 26 percent of the patients were managed at home by the poison center without complications. More than a third of the patients remained asymptomatic, 50 percent had minor effects, and seven percent (six) patients had severe effects. Only those with follow-up were included in the analysis. There were no fatalities. The most common clinical effects were those suspected from an opioid: drowsiness, lethargy, vomiting, and miosis. Respiratory depression was seen in six children, and coma occurred in two. It required about an hour for symptoms to become obvious in those who developed them, but symptoms were delayed up to three hours in a few cases. Although the study suffers from reporting bias, relied on historical recall, and lacked laboratory confirmation, the mean dose of BPN ingested was reported as 3 mg. Tablets are available in 2 mg and 8 mg strength. Sublingual Subutex is a white tablet; Suboxone is an orange tablet. One child was reported to have ingested 24 mg, and those ingesting the higher doses tended to have more significant symptoms. A 4 mg dose was apparently benign in all cases. In this retrospective analysis, a 4 mg ingestion

By James R. Roberts, MD Author Credentials and Financial Disclosure: James

R. Roberts, MD, is the Chairman of the Department of Emergency Medicine and the Director of the Division of Toxicology at Mercy Health Systems, and a Professor of Emergency Medicine and Toxicology at the Drexel University College of Medicine, both in Philadelphia. All faculty and staff in a position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity.

Part 2 in a Series
appeared to be the cutoff for concern or need for a mandatory EP evaluation (gutsy move, if you ask me). Minimal gastric decontamination was initiated. One patient did require intubation and mechanical ventilation. About one-quarter of the patients received naloxone, and the vast majority had some response. Dosing parameters were vague because the dose or indication for naloxone was not recorded in all cases. It has been reported that large doses of naloxone, sometimes 10 times the standard dose, is required to reverse BPN respiratory depression. The authors note that BPN overdose is essentially an opioid overdose, and it produces CNS and respiratory depression, miosis, and occasional vomiting. Prior reports have demonstrated that accidental oral BPN overdose, even in children, is usually quite benign. Serious toxicity is not to be expected, and was not seen if less than 4 mg were ingested. Because the drug can be dispensed in an 8 mg tablet, the potential for toxicity in a small child is obvious. Although the most common product ingested was the buprenorphine-naloxone combination, the naloxone has no protective anti-opioid effect when taken orally. Only one child required mechanical ventilation, and two were treated with naloxone infusions; the exact reasons for these interventions were unclear. These authors highlight the usual benign course of an accidental pediatric BPN ingestion, and believe that those merely exposed to a taste of the tablet, even the 8 mg dose, can be safely observed at home. This assumes, of course, reliable parents and a perfect history. Because BPN is usually administered sublingually, swallowing the pill is expected to decrease bioavailability. The duration of clinical effects was between two and eight hours in most patients. The drug does have a long serum half-life, so prolonged observation may be required if significant symptoms are present within the first few hours or if they persist. The potential for delayed onset of CNS and respiratory depression is highlighted, although symptoms will likely develop within two to three hours postingestion if a significant exposure has occurred. The authors suggest a minimum of six hours observation for children exposed to BPN orally, with discharge from the hospital being appropriate if there are no clinical concerns at the six-hour mark. Continued on next page

Learning Objectives: After reading this article, the physician should be able to: 1. Describe the toxidrome associated with buprenorphine overdose. 2. Explain buprenorphines potential for respiratory arrest. 3. Outline the proper use of the reversal agent naloxone. Release Date: January 2009

pioid addiction is rampant in this country, and a shift does not go by without at least two or three patients trying to score narcotics by ingenious methods. As I noted last month, buprenorphine (BPN) is the latest drug to fight those addictions, and it is quickly becoming the European substitute for methadone maintenance. I have seen a few patients on BPN maintenance, and they are not particularly problematic. Interestingly, BPN is abused more than cocaine, GHB, or ecstasy in Scandinavian countries, where it has gained great popularity as a street drug. Snorting or injecting the non-naloxone preparation is a common recreational activity in Europe, but it has not yet reached great proportions in the United States. But its only a matter of time until U.S. addicts catch on. BPN cannot be detected by a urine drug screen, and I can envision it gaining use for affluent oxycodone addicts whose private physicians address addiction in a manner more civilized than the local methadone clinic. I introduced BPNs pharmacology last month, and this month will focus on overdose and unintentional adverse effects. Toxicity of Buprenorphine Overdose in Children Hayes BD, et al Pediatrics 2008;121(4):e782

Reported Effects of Accidental or Unintentional Oral Buprenorphine Exposure in 86 Children1

Effect None/asymptomatic Some toxicity Significant CNS/respiratory depression Drowsiness or lethargy Vomiting Miosis Agitation or irritability Pallor Coma Cyanosis Hypotension Ataxia Naloxone administered Mean age Occurred at home Treated at home Treated in hospital No. of Patients (%) 32 (37) 54 (63)2 6 (7) 47 (55) 18 (21) 18 (21) 4 (5) 3 (3) 2 (2) 1 (1) 1 (1) 1 (1) 21 (24)3 2 years (9 months 5 years) 83(96%) 22 (26%) 64 (74%)

1. Some cases (2 mg or less exposure) were managed at home. 2. There were no fatalities. 3. Two patients received continuous infusion. Adapted from Pediatrics 2008;121(1):e782.

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January 2009

InFocus
with a reliable (I say, pristine) support system, including reliable parents, transportation, and ability to closely observe. Those suspected of significant BPN exposure should be monitored in the ED for six hours, at which time asymptomatic patients can be safely discharged.

BUPRENORPHINE
Continued from previous page It was the authors experience that naloxone successfully reversed BPN. It has been stated that exceptionally large doses are required, but that was not confirmed in this study. Due to a paucity of reporting data, accurate naloxone dosing regimens cannot be forthcoming. It was emphasized, however, that the duration of action of naloxone is significantly less than that of BPN. If naloxone is used as a reversal agent, the authors suggest continued observation (not quantified) and perhaps even a continual IV infusion. Given the increased use of BPN for opioid addiction, the potential for accidental childhood exposure will likely increase. Parents take this drug home, and the orange pill is inviting to a toddler. Interestingly, a veterinary product in an injectable form is available for pain relief in pets, and was involved in some of the exposures in this report. Although limited by retrospective data, the authors conclude that unintentional BPN ingestion is generally well tolerated in children, with respiratory depression being unusual. They suggest that an exposure documented to be greater than 2 mg in a child under 2 should be referred to the ED for evaluation. Others can be observed at home

Comment: This article confirms prior

reports that accidental oral BPN exposure is relatively safe when compared with the serious consequences of morphine or methadone ingestion in children. While BPN has narcotic effects, this drug only partially stimulates the mu receptors, resulting in clinical effects similar but significantly less than morphine or methadone. One would expect the child or adult overdosing on this product to have a classic narcotic toxidrome (miosis, sedation, respiratory depression, decreased bowel sounds, urinary retention, and perhaps bradycardia and hypotension). The delayed onset of BPN clinical activity is highlighted, but the overall safety of the standard 2 mg tablet, even in a small child, is reinforced. Poison centers should be congratulated on their evidence-based approach to phone consultations for children exposed to BPN. I would always opt for hospital observation in all but the most straightforward cases. I am not sure I consider any parent to be reliable if he is taking BPN. He is, by definition,

What toddler can resist this tempting brightly colored morsel? Ingesting an 8 mg tablet will likely not be fatal to a child, but more than 2 mg to 4 mg can be expected to cause some symptoms. If a BPN overdose is suspected and any symptoms are significant, administer large doses of naloxone before considering another alternative, such as intubation.

an opioid addict. One also wonders if any other recreational opioids were left in the house, such as Percocet, methadone, or heroin to provide a supplemental buzz in opioid patients who continually seek a narcotic high. I agree with foregoing GI decontamination because naloxone is effective

and readily available. I found it interesting that swallowing the sublingual pill probably decreased systemic effects. Swallowing the pill also may decrease GI motility, likely accounting for the one to two hours of delayed symptoms. It appears reasonable to support a sixhour observation status, with discharge

Reader Feedback:
Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com. Dr. Roberts requests feedback on this months column, especially personal experiences with successes, failures, and technique.

Dr. Roberts: I appreciate your attempts

to address the issues about fluoroquinolones, but I wanted to note that the adverse reactions to this class are not allergic reactions. They are reactions that persist for years after the medication has been discontinued, or they become lifelong disabilities to which there is no known treatment. Irreversible peripheral neuropathy and chronic tendonitis are two such examples. Bizarre? Yes. Unexpected? No. These are published adverse reactions associated with this class since 1982. Considering that more than half of these drugs have been withdrawn, and

thousands of articles have been published in the leading medical journals describing these adverse reactions, one would think they would be anything but unexpected. In a recent study, it was shown that of 204 fluoroquinolone patients, 122 experienced one or more adverse event. This is greater than 50 percent. In the new drug application for Levaquin, we find the adverse reaction rate exceeding 40 percent, including fatalities. Bayer issued a Dear Doctor letter in Europe concerning Avelox and the risk of developing fulminant hepatitis, leading to liver failure and bullous skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis). We see no such a letter issued here in the United States. Canadian authorities are investigating this same association with Levaquin. More than half of the drugs found in this class have been removed from clinical practice due to toxicity issues: Trovan, Raxar, Tequin, Sparfloxacin, and Temafloxacin, to name a few. The FDA also decided that Gemifloxacin should be studied further due to reports of severe disfiguring skin reactions. In numerous studies, it has been shown that there is a definitive asso-

ciation between fluoroquinolone use and Clostridium difficile-associated disease. One also has to consider the total numbers from MedWatch from November 1997 through May 2007, which contain fewer than two percent of the actual events and excludes all reports prior to 1996. It reports 180,802 reactions, 3,325 deaths, and 43,933 individual safety reports. This is not the safety profile of a well tolerated drug. This is a profile of a toxic chemotherapeutic agent that has been subject to a ridiculous amount of scripting abuse and that has been destroying lives needlessly since 1982. QTc prolongation is not a remote connection; it has been reported since 1996. This was discussed within the new drug application for Avelox, and the medical officer stated that it is hard to justify approving this agent as first-line therapy for non-life-threatening infections [for] which there are a plethora of treatment choices. The majority of the members of the advisory committee voted not to approve Avelox due to QTc. The sponsor provided questionable data to the FDA that showed that Avelox on average only prolonged the QTc about 4 msed.

But about 90 percent of the patients were excluded from this evaluation, and the ECG was obtained as late as six hours after drug intake. When corrected, these data showed changes in QTc intervals greater than 80 msec over baseline with resulting QTc intervals above 500 msed. During preclinical animal toxicological assessment, all fluoroquinolones have been proven to prolong the QT interval. In studies submitted to the FDA, arthropathy occurred more frequently in fluoroquinolone patients. The affected joints included knee, elbow, ankle, hip, wrist, and shoulder. Arthropathy was seen in 9.3 percent of patients at six weeks. The rates were 13.7 percent at one year. In another study, the one-year rate was 13 percent. A multicenter, observational, comparative cohort study conducted between 1998 and 2000 showed musculoskeletal adverse reactions occurred more frequently in the fluoroquinolone group (3.8%) than in controls (0.4%). The consumer advocacy group Public Citizen filed a petition back in 1996 demanding black box warnings as well as Dear Doctor letters concerning these issues. The Illinois attorney general

InFocus
of asymptomatic patients. Importantly, the added naloxone has no protective effect for opioid toxicity when the pill is taken orally. It seems reasonable to administer naloxone as a universal empiric antidote in children who have signs and symptoms of significant opioid toxicity. There are no downsides. There is sparse literature suggesting that large doses of naloxone may be required for this overdose because BPN is tightly bound to the mu receptor. This seems to be a reasonable and prudent safeguard, and I would use up to 10 mg of naloxone in a child who may have been exposed to any opioid before quitting. BPN will not be found on a drug screen even though it is an opioid. Methadone is also absent from most hospital drug screens, as is Lomotil, propoxyphene (Darvon), meperidine (Demerol), and fentanyl (Duragesic patch), and contrary to popular belief, oxycodone also often escapes detection by immunoassay. When the scenario looks, walks, and smells like an opioid overdose, bring out enough naloxone to adequately reverse some of these more esoteric ingestions. In a patient who has a good response to naloxone, a constant infusion is a reasonable intervention if the patient requires either repeat reversal or hospital admission. I suspect some clinicians simply administer naloxone to a toddler as prophylaxis just in case a narcotic was ingested. I dont think thats a great idea. One argument for withholding naloxone, even in a minimally symptomatic patient, is that you can follow the case clinically and act accordingly. You are not bound to a longer observation time or a mandated admission. After about an hour, any standard dose of naloxone reversal should wear off, and you are left with a snapshot of any residual (unopposed) opioid effects, and can then decide on the next step. With large naloxone doses (more than 1-2 mg), the pharmacokinetics become more confusing, and longer observation is required to be sure the naloxone reversal has dissipated. I suspect that some of the infusions were empiric in this study, and not just for those requiring a second bolus. There is no standard for specific naloxone doses nor strict criteria for a continuous infusion. The mechanics of a constant infusion are pretty much guesswork anyway. I suggest considering the intervention if a second naloxone reversal is needed for a return of serious opioid toxicity. Calculate two-thirds of the naloxone required to obtain the desired reversal level, and administer that dose by constant infusion. Simply put a whole bunch of naloxone in a bag of saline, and dial up the infusion pump. This is not rocket science. The only downside to a constant infusion is that the adult with opioid addiction will continue to be in withdrawal during the infusion, and most will not tolerate it. Those cases are probably better handled by small doses of naloxone to stave off respiratory depression in a monitored setting, rather than have to deal with a very unhappy addict who is bent on leaving. Other authors have chronicled serious BPN overdose after unintentional ingestion in children. Cho et al (Ann Emerg Med 2006;48[1]:109) report a child who apparently is typical of a serious but unusual BPN accidental overdose in pediatrics. This 9month-old was found near an open bottle of Suboxone (8 mg BPN/2mg naloxone). The parents obtained the medicine illicitly to treat their own oxycodone addiction. Per reports, only one pill was missing. About 30 minutes after ingestion, the child demonstrated decreased mental status and slow, shallow respirations, and was unresponsive to 1 mg of IV naloxone. After a total dose of 5 mg naloxone, the child experienced reversal of somnolence, and maintained a normal respiratory effort. It took about 48 hours for the childs mental status to return to normal. BPN was found in the urine, and no other narcotics were present. My analysis is this child could have died from respiratory arrest had he not received

January 2009 EMN 9

medical attention. This brings up the issue of treating children at home because of the difficulty in reliably judging parents over the phone and the perceived safety of this drug. But such an approach appears a common poison center practice when the actual exposure can be quantified. Assuming that only a single 8 mg tablet was ingested, the 5 mg naloxone dose required for reversal is an important finding. Although other cases have described rapid improvement with relatively small doses, there is a general theme in the literature that large naloxone doses are required. Death Involving Buprenorphine: A Compendium of French Cases Kintz P Forensic Sci Int 2001;121(1):65 This paper is a retrospective survey of a two-year period in a number of French forensic centers. Buprenorphine has been used for more than 20 years in Europe as an analgesic, and more recently as substitution management of opiate dependence. Since 1966, sublingual tablets in doses as high 8 mg have become available as an alternative for methadone maintenance. It appears that any physician in France can prescribe up to 28 days of Subutex, and the drug can be Continued on next page

filed a similar petition in 2005, and Public Citizen filed yet another one in 2006, all seeking the same warnings that were requested a decade ago. It was not until Public Citizen filed a lawsuit in Federal Court in January 2008 to compel the FDA to review these petitions that the FDA responded. In June, the FDA requested black box warnings. They did not mandate them, as you stated. And no Dear Doctor letters were sent, but rather notification was made on a web site (hcnn.net) that is only available to physicians who register on that site. Nothing was sent by mail. Five months later, we finally see the Black Box warnings, but they are as pathetic as the original warnings. The litigation in Federal Court continues, and the Illinois attorney general plans further action as well. You also didnt mention that irreversible peripheral neuropathy has been documented since the 1980s associated with Pefloxacin (1990, 1995); Sparfloxacin (1992); Ciprofloxacin (1988, 1990, 1992, 1993, 1994, 1995, 1996); Ofloxacin (1993); Moxifloxacin (2000, 2001, 2002); and Avelox and Tequin (2002). You noted that patients who receive quinolones

in the ED range from those with mild cystitis to those with full blown sepsis. Not true. Fluoroquinolones are routinely handed out like Halloween candy for inappropriate indications in the ED setting. A recent study stated that 99 percent of the time, the prescription was in error. Of 100 total patients, 81 received a fluoroquinolone for an inappropriate indication. Of the 19 patients who received a fluoroquinolone for an appropriate indication, only one received the correct dose and the correct duration of therapy. Your comment regarding lawsuits is also in error. There are currently only 33 lawsuits filed involving Levaquin, which have been combined via multidistrict litigation. But considering the fact that the warnings are grossly inadequate and that the manufacturers have refused to add the black box warnings that were requested 12 years ago or to send out Dear Doctor letters, one can expect tens of thousands more. For someone to state that 10 years of reports found on various Internet fluoroquinolone adverse drug reaction forums are to be considered wacky is shameful. I invite you to log on to www.fqresearch.org to review the more than 4,000 published

medical journal entries found there before insulting these patients in this manner. David T. Fuller, Director, Fluoroquinolone Toxicity Research Foundation

Dr. Roberts responds: I appreciate your letter. Obviously, you are passionate about this topic, and have great personal interest. I know your organization serves as a sounding board for patients and as a data collection agent, soliciting self-reporting. I wonder if you or your foundation serve as an expert witness on this subject, for one or both sides? With regard to me feeling shameful by labeling some associations wacky, one thing does trouble me regarding your fervor. I note on Google that your web site refers readers to free lawyer consultations and clinics specializing in treatment of these (supposedly nonwacky) adverse reactions, so I am not sure you are truly unbiased (no offense intended). I am aware that the discussed reactions are not allergic. Lowly clinicians such as myself, sans a web site, have not seen countless patients mangled, killed, or crippled by quinolones, and do not expect such complications from

antibiotics. I did call for a rethinking of reflex-prescribing of all antibiotics, eschewing the Halloween candy reference; we agree on this one. I maintain that such reactions are not common knowledge, hence the original purpose of my column. To illustrate: On one of your Internet postings, in answering a physicians inquiry, you note the doctors total lack of knowledge you have regarding the damage this class of antibiotics can and will do. I do think you were a bit harsh by labeling the commenter but another ignorant and arrogant physician who is a clear and present danger to those you treat. I have had a few comments on my article, mostly from colleagues who were astounded at the severity of potential reactions, usually commenting that they had not encountered them, despite being frequent prescribers, hopefully now reformed. Per your suggestion, I did go to www.fqresearch.org, but stopped reading when I read: Having been abandoned by the media, the medical community, the FDA, and as well as Congress, it appears that the lawyers are the only ones who give a damn. How nice that the lawyers truly care when doctors are so callous.

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January 2009

InFocus
I would not be surprised to see more BPN issues in the ED, given the rise in its popularity, its increasing availability, and its perceived wide margin of safety. One might be confused by an opioid toxidrome with a negative drug screen unless the drug has been identified by history. Similar events will be seen with methadone, fentanyl, propoxyphene, meperidine, and other opioids (often even oxycodone) that do not show up on a standard urine drug screen. I know of no hospital that can test for BPN. The bottom line for clinicians is a strategy to treat narcotic-appearing overdoses with large doses of naloxone, even in the presence of a negative drug screen for opioids.

BUPRENORPHINE
Continued from previous page obtained at a pharmacy and taken home. Unlike methadone maintenance, patients do not have to take the drug while being observed, and urine testing to screen for additional opiate use is not mandatory. As one would suspect, BPN is now on the black market and a street drug, but overall the program has been deemed successful. Of particular interest is the observation that the number of fatal heroin overdoses dropped precipitously following the drugs introduction. A handful of BPN-related fatalities (117 in this report) have been reported in France, and in almost all cases, supplemental drugs, usually benzodiazepines, also were abused. The cause of death appeared to be respiratory arrest because no other cause could be established by the pathologist. This study is hampered by the fact that no lethal or toxic concentrations of BPN are available in a database. Although BPN was found in the blood of fatalities, the authors document that at least one other potentially fatal drug was always present. The major conclusion was that BPN can be fatal in overdose when associated with other abused medications, most commonly benzodiazepines. The route of administration was usually IV, and recent injection sites were found in more than half of the fatalities. Chronic use was confirmed by hair analysis in a significant number of patients. The authors conclude that fatalities involving BPN alone are very unusual. They highlight the dangerous role of associated benzodiazepine use, and suggest but do not prove that there may be a synergistic depressant effect of the two drugs. The IV use of the sublingual tablet or massive oral overdose was postulated on all fatalities.

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January 2009
Questions: 1. Oral BPN with naloxone can cause respiratory arrest, but it has a better overall safety profile than other opioids. True False 2. Buprenorphine will register as an opioid on a standard immunoassay urine drug screen. True False 3. The naloxone component of the BPN-naloxone tablet inhibits respiratory depression in an oral overdose. True False 4. Its reasonable to administering large doses of naloxone, up to 10 mg to 20 mg, if a BPN overdose is suspected. True False 5. Crushing a sublingual BPN-naloxone tablet and injecting it intravenously can cause respiratory arrest. True False Your evaluation will help us assess whether this CME activity is congruent with LCMEIs CME mission statement and will assist us in future planning of CME activities. Please respond to the following questions: 1. Did the content of this CME activity meet the stated learning objectives? Yes No 2. On a scale of 1 to 5, with 5 being the highest, how do you rank the overall quality of this educational activity? 5 4 3 2 1 3. Was the activitys format (i.e., print, live, electronic, Internet, etc.) an appropriate educational method for conveying the activitys content? Yes No 4. Did this CME activity increase your knowledge/competence in the activitys topic area? If No, please explain why not. Yes No __________________________________________________ 5. As a result of participating in this CME activity, will you be changing your practice behavior in a manner that improves your patient care? Please explain your answer. Yes No __________________________________________________ 6. Did you perceive any evidence of bias for or against any commercial products? If yes, please explain. Yes No __________________________________________________ 7. How long did it take you to complete this CME activity? _____ hour(s) ____ minutes 8. Please state one or two topics that you would like to see addressed in future issues. ___________________________________________________

Comment: This is a rather vague article, but one that is frequently quoted. The methods and data are too imprecise to draw firm conclusions other than some people were found dead with BPN in their blood. BPN alone and benzodiazepines alone have a wide margin of safety, but the combination has been frequently quoted as being particularly lethal. I could find no real science behind this contention; it may merely reflect the polysubstance abuse of addicts. Of most importance is that BPN is now more popular than cocaine, ecstasy, and heroin in some European countries. It is easy to obtain, currently quite fashionable, popular with opioid aficionados, and apparently associated with a quite pleasurable high when injected or snorted.

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