Best review from NEJM (2012;367(2):146)
Laudanum was tincture of opium, opium + ETOH
“I’ve never woken somebody with Narcan that I actually wanted to talk with.”
Heroin lasts 4 hours
Morphine up to 24
Propocyphone (Darvon)-very easy to overdose, causes seizures
Diphenoxylate-Lomotil, has atropine added to prevent abuse
Codeine-needs to be metab. to morphine, some people can not do this and get side effects
Darvon, Demerol, Ultram-all can cause seizures in overdose
MPTP-the designer opioid that caused Parkinsons
Nalaxone-give if resp<12 and signs of opioid overdose. Give in doses of .04 mg (dilute one vial in 10 cc syringe) Give 2/3 dose needed to reverse per hour. The 2/3 was based on work by Goldfrank (Ann Emerg Med 1986;15(5):566/91). His study demonstrated we should give load, then start a drip at 2/3 of that dose per hour. A second bolus should be given at 1/2 the loading dose at the 15 minute mark.
Nalmefene-4-8 hrs give .5 mg may repeat q 2-5 minutes. Start at .1 mg in opioid dependant patients
Naltrexone-up to 72 hours
The duration of action of naloxone is approximately 45 to 70 minutes (Circulation. 2010;122:S829).
long acting, give it to block sites for heroin, keep increasing dose until pts stop testing heroin positive in urine
Decreased respiratory rate, normal Vt
Methadone is structurally similar to verapamil, and can cause calcium channel blockade resulting in bradycardia by acting on the same receptors (Journal of EM, July, 2005, pg. 74).
peak 2-4 hours
Methadone is a long-acting narcotic pain medication commonly used in the treatment of heroin addiction. The two most common reasons for long-term usage are chronic pain and opiate dependence. Although methadone has been used for more than 40 years, it has only recently been linked to cases of Tdp.[1,2] Prolongation of the QT interval predisposes patients to the dysrhythmia. Katchman and colleagues report that methadone can block the specific cardiac channel responsible for ventricular repolarization (the human ether-a-go-go or HERG potassium channel); this mechanism causes QT prolongation and explains the development of Tdp. Dose-related increases in the QTC interval have been documented in patients begun on methadone with and without a history of Tdp.[4,5,6]
In April of 2001, the European Agency for the Evaluation of Medicinal Products announced the withdrawal of levactylmethadol, a methadone derivative, from the market after associating the drug with seven cases of Tdp. The following year, Krantz et al. published a series of 17 cases of Tdp in methadone-treated patients. All patients presented with overt syncope. Daily methadone doses were substantially higher than average but ranged from 65 to 1000 mg/day. The QTC intervals were at least 500 ms in all patients. Fourteen of the 17 patients had other predispositions to dysrhythmias, including hypokalemia, hypomagnesemia, or treatment with other medications known to prolong the QT interval or inhibit methadone metabolism. Fourteen patients were successfully treated with implantable cardioverter-defibrillators.
Walker et al. published a report of three cases of Tdp in patients on daily doses of methadone exceeding 600 mg who presented to the ED of a single hospital during an 8-month period. Two patients presented with syncope and one with respiratory distress. Each of the three was on other medications that inhibit the metabolism of methadone, suggesting drug-drug interactions contributing to development of the dysrhythmia.
After publication of the previously described reports, Pearson and Woosley did a retrospective analysis of adverse events attributed to methadone that were reported to the Food and Drug Administration from 1969 to October 2002. Forty-three patients (.78%) noted Tdp and 16 (0.29%) noted QT prolongation. Only three of these observations were before 2000, underscoring the recent recognition of this association. The mean daily methadone dose was 410 mg, with a range from 29 to 1680 mg. Forty-four (75%) of the patients had other risk factors for the dysrhythmia, including interacting medications, hypokalemia, hypomagnesemia, structural heart disease, and female gender. The authors noted that methadone has bradycardic properties. Previous observations identify bradycardia as a trigger for Tdp.[9,10] The authors suggest that methadone toxicity, traditionally attributed to respiratory depression, may be partially mediated through cardiac toxicity.
There are a number of possible explanations for the seemingly recent emergence of the association between methadone and Tdp. These include changes in the dosage of the drug, with increasingly higher mean doses used in recent years. The preponderance of reported cases in patients on very high doses adds credence to this hypothesis. Another possibility is that newer drugs taken by methadone patients have precipitated dangerous drug interactions when used with methadone, including prolongation of the QT interval. It is also possible that Tdp is not a recent toxic effect of methadone but was unrecognized before the late 1990s.
Because patients taking methadone are commonly seen in the ED, it is important to be aware of the cardiotoxic effects of the drug; methadone toxicity should be considered in the differential diagnosis of Tdp and its clinical manifestations. An ECG is not always performed during the evaluation of a young patient presenting with a seizure. We believe that it should be considered if the patient is taking methadone.
Our patient manifested syncope and seizure activity while demonstrating classic Tdp. We believe that her high daily methadone dose is the most likely explanation. We do not believe that concurrent metoprolol therapy was a contributing factor for Tdp for two reasons. First, our patient presented with tachycardia (120 beats/min), not bradycardia, which is a side effect of metoprolol known to predispose to Tdp. Second, consideration of the metabolism of methadone and metoprolol does not support a significant drug-drug interaction between the two medications in our patient.
Methadone is primarily metabolized by certain cytochrome P450 (CYP450) enzymes. These enzymes are primarily found in the liver, but also may be present in other organs. There are over 28 CYP450 enzymes that are designated by a combination of numbers and letters. CYP3A4 and CYP2B6 are the most important enzymes in methadone metabolism, with CYP2D6 having a secondary role. In addition, CYP1A2 may play a role. When considering the possibility of a drug-drug interaction in our patient, it is worth noting that metoprolol is a CYP2D6 substrate and methadone is a moderate inhibitor of CYP2DD6. This interaction, therefore, would be expected to increase the effects of metoprolol. Given that our patient was hypertensive and tachycardic, it is unlikely that this was a significant interaction for her.
Alcohol was another co-ingestant; we were unable to find a direct association between Tdp and holiday heart syndrome. Our patient had a slight hypomagnesemia possibly related to alcohol use; severe hypomagnesemia is a risk factor for drug-induced Tdp.
She responded well to cardioversion and treatment with intravenous magnesium sulfate and lidocaine. Definitive management included reduction of daily methadone dose and implantation of a cardioverter-defibrillator. The latter was placed for protection against further life-threatening dysrhythmias. The reduction in our patient’s methadone dose shortened her QT interval but the cardiologist believed the device was indicated. The patient’s history of heroin addiction mitigated against successful management without continued methadone therapy.
Methadone and QT ProlongationA large body of evidence suggests that methadone is associated with QTc interval prolongation and torsade de pointes (1). This association received attention when the FDA issued a physician safety alert regarding increasing deaths and cardiac arrhythmias, which was followed by a manufacturer’s black box warning (2,3).
This association is of significance to the Emergency Physicians for two reasons: (1) When evaluating a patient with TDP or prolonged QTc, consider methadone as the etiology and (2) when prescribing medications that are known to prolong the QT interval, it behooves the physician to consider whether the patient is taking methadone.
Drugs that are known to prolong the QT interval
References:(1) Krantz MJ, et al. QTc Interval Screening in Methadone Treatment Ann Intern Med. 17 March 2009; Volume 150. [Jan 19. Epub ahead of print](2) Methadone hydochloride (marketed as Dolophine) information: death, narcotic overdose, and serious cardiac arryhythmias. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; November 2006. www.fda.gov/cder/drug/infopage/methadone/default.htm (3) Dolophine Hydrochloride CII (Methadone Hydrochloride Tablets, USP) 5 mg, 10 mg, Rx Only. Columbus, OH: Roxane Laboratories; 2006. www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf
Can we discharge patients after nalaxone administration (CJEM 2000;2(3)) Poor methodology-observational study would indicate that we know who needs to stay for whatever that is worth.
Best semi-SR (EMJ 2005;22(9))
Since the half life of naloxone is 6090 minutes, it would seem logical to observe patients for signs of recurrent toxicity for at least 2 hours, although further studies are needed to validate this.
Clenbuterol Overdoses The Maryland Poison Center was notified recently that the states of New Jersey, Pennsylvania and Illinois are reporting cases of clenbuterol contamination of heroin. Clenbuterol is a β2 receptor agonist (think Ventolin®) with rapid onset and long duration of action. It is approved for limited veterinary use in United States. Clenbuterol is also used illicitly as an alternative to anabolic steroids in humans and animals to increase muscle mass. A case series of 26 clenbuterol/ heroin exposures on the east coast was reported in 2005. It remains unclear whether clenbuterol contaminated the heroin or was substituted for heroin in this 2005 case series.1 Clinical effects of clenbuterol intoxication include: agitation, tachycardia, hypotension, hyperglycemia, hypokalemia and venous hyperoxia. Management of clenbuterol exposures is symptom-driven. Decontamination is usually not required because the exposures have been parenteral. Benzodiazepines have occasionally been used to treat agitation and tachycardia. Fluids should be administered to treat hypotension. Mild and short-lived electrolyte abnormalities do not require correction unless they cause life-threatening changes. Hospitalization is recommended for symptomatic individuals because of the very long duration of action. Some patients were hospitalized for a total of 5 days following the 2005 epidemic. Clenbuterol cannot be detected in traditional substances of abuse screening tests. PLEASES NOTIFY THE MARYLAND POISON CENTER OF ANY SUSPECTED or KNOWN OPIOID OVERDOSE. Suzanne Doyon, MD Medical Director 1. MMWR. Atypical reactions associated with heroin usefive states, January-April 2005. Aug 19, 2005/54 (32);793-796.
Heroin Induced Acute Lung Injury
Non-cardiogenic pulmonary edema is the old term, ALI is a better description.
from huge catecholamine surge after reversal b/c of respiratory centers response to high PaCO2, bag the patient before narcan to blow off CO2
Histamine release-vasodilation, urticaria
1 mg narcan should reverse 25 mg morphine
Clonidine then naltrexone
One study looked at heroin ODs in the field who after reversal refused transport. Some received IV reversal then an IM shot. No deaths were found (exam of all morgue records) in ~1000 patients in the study. (Acad Emerg Med 10(8):893, Aug 2003)
Chasing the Dragon
burn the heroin in tin foil then inhale. Rarely, can get encephalomalacia. No white matter, brain fried. Toxic spongiform leukoencephalopathy
Fentanyl and Analogues
Sometimes substituted for heroin with many resultant deaths
China White and Tango & Cash
Does not show up on tox screen
Needs much higher doses of nalaxone
Fast sodium channel blockade resulting in wide complex dysrhythmias
Responds to lido and Bicarb, but not nalaxone
Heroin+Scopolamine (Polo, Homicide, Sting)
After reversal, signs of ACh toxicity
can get wound botulism-especially from black tar heroin, a crude form mainly produced in Mexico and skin-popped or IM injected. No GI symptoms. Dry mouth, blurred vision, and diplopia. Symmetrical descending paralysis.
Rapid detox centers now offer same day detox. Some use naltrexone pellets, numerous side effects have been reported (Acad Emerg Med)
Can also cause R sided endocarditis and pneumonia
Hallmarks: mydriasis, piloerection, increased bowel sounds, tachycardia, yawing, hyperthermia, lacrimation, rhinorrhea, n/v/d, myalgias, only neonates seize, Normal Mental Status
(Most reliable b/c they can not be faked: mydriasis, piloerection. Quiet bowel sounds=no withdrawal)
Methadone 10 mg IM or 20 mg PO will stop withdrawl
Clonidine bolsters methadones effects. .1 to .3 mg PO q hour until sx resolve then .3 mg BID or TID
The recent approval of office-based treatment for opioid addiction and US Food and Drug Administration approval of buprenorphine will expand treatment options for opioid addiction. Buprenorphine is classified as a partial opioid agonist and a weak antagonist. It has a high affinity for the receptor, with slow dissociation resulting in a long duration of action and an analgesic potency 25 to 40 times more potent than morphine. At higher doses, its agonist effects plateau and it begins to behave more like an antagonist, limiting the maximal analgesic effect and respiratory depression. This “ceiling effect” confers a high safety profile clinically, a low level of physical dependence, and only mild withdrawal symptoms on cessation after prolonged administration. Suboxone contains a mixture of buprenorphine and naloxone. The naloxone is poorly absorbed sublingually and is designed to discourage intravenous use. Subutex, buprenorphine only, will also be available primarily as an initial test dose.
Buprenorphine: A Drug You Need to Know About [InFocus]
Roberts, James R. 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.
Learning Objectives: After reading this article, the physician should be able to:
1. Explain the pharmacology of buprenorphine (BPN).
2. Describe BPN’s role in treating opioid addiction.
3. Outline the potential side effects of buprenorphine.
Release Date: December 2008
A plethora of new and complicated drugs come to the market each year, many of which have only incidental importance to the emergency physician. Buprenorphine (BPN) is not one of them. This drug has been around for a number of years, but has mainly garnered its reputation in the drug addiction literature, primarily for the treatment of opioid addiction in Europe. BPN is becoming the European substitute for methadone maintenance.
But BPN has recently become available, and is gaining use in the United States. In 2002, with the enactment of the Drug Addiction Treatment Act, Title XXXV, it became legal to prescribe BPN in a physician’s office for opioid addiction. As with any other drug with CNS effects, the potential for abuse or overdose has emerged. BPN is an occasionally used opioid analgesic (Buprenex), but the FDA has approved BPN for treatment of opioid dependence, usually heroin addiction. For this indication, BPN has a clinical use profile similar to methadone. Both methadone and BPN are potent narcotics, quell the craving for heroin, and are addictive in their own right, but they have some unique differences. Most EPs have not yet encountered this drug in real life, but it’s only a matter of time until you will be faced with BPN issues in your practice.
The Clinical Pharmacology of Buprenorphine: Extrapolating from the Laboratory to the Clinic
Walsh SL, Eissenberg T
Drug Alcohol Depend
Figure. Suboxone sublingual tablets are also referred to bupe (from buprenorphine). Subutex (BPN) is a white tablet, and Suboxone (BPN/naloxone) is orange, above. Both are sublingual preparations, in either 2 mg or 8 mg strength.
This article is an extensive review of the clinical pharmacology of buprenorphine (BPN), a mixed opioid agonist-antagonist. Similar to methadone, BPN is currently approved for treating opioid dependence in an effort to keep addicts from wanting or using illicit narcotics. BPN has some advantages and some disadvantages as an opioid maintenance agent, and its pharmacology is not particularly straightforward at first glance. Methadone is an opioid agonist, meaning that it simulates the effects of heroin and morphine by stimulating the same receptors as do those potent narcotics.
BPN, on the other hand, stimulates and antagonizes (blocks) opioid receptors, giving it some unique properties. Stimulation of the opioid mu receptor is the pharmacologic process by which most narcotic effects emerge. Central and spinal mu receptor stimulation relieves pain and produces respiratory depression but also causes euphoria. Kappa and delta receptors also have physiologic function. (See table.) BPN is a partial mu agonist, with minimal kappa antagonism. The therapeutic benefit and side effects of morphine are derived largely from morphine’s action on the mu receptor.
Because it is only a partial mu agonist, BPN’s clinical effect will always be less powerful than that which can be produced by a full mu opioid agonist, such as morphine or methadone. BPN is bound rather tightly to the opioid receptor, and it can be difficult to separate it from this receptor by metabolism or reversal agents. Bottom line: When compared with heroin or morphine, BPN has similar but less potent opioid effects and a longer duration of action.
Safety Profile: As with any other opioid, large doses of BPN can cause direct respiratory depression, which can be fatal. Compared with morphine, there is a wide margin of safety with BPN because of its lower intrinsic activity, otherwise known as partial mu receptor agonism. While BPN fully occupies the morphine receptors, it has less activity while doing so, and so is a safer drug in overdose. BPN has minimal pain relief when compared with methadone, but as maintenance therapy for opioid addiction, BPN certainly has a much better safety profile than methadone.
BPN can depress respiration, but curiously the respiratory depression from BPN does not increase linearly as higher doses are given. administering 32 mg of BPN, for example, produces no greater respiratory depression than administering a 16 mg dose, making it a safer drug in overdose. BPN may be even safer in opioid-tolerant individuals who tend to require large and escalating doses for a similar effect. There are, in fact, few reports in the literature of death from respiratory depression by BPN use alone. As is common with drug-dependent individuals, polysubstance abuse (particularly concomitant opioid, benzodiazepine, or alcohol ingestion) can make BPN a more potent medication. Like other opioids, BPN also can cause constipation, urinary retention, miosis, sedation, and behavioral impairment.
Pharmacology of BPN: BPN has a pharmacology profile similar to other mu agonists, and it produces an array of clinical effects, such as sedation and euphoria. One can get a narcotic high by using BPN that is intensified by IV administration. Given the partial agonist activity of BPN, however, the magnitude of these sought-after effects (AKA abuse potential) is limited, and possibly may be associated with a lower abuse potential. The clinical effects can last for up to 24 to 48 hours, with higher doses producing more sustained effects. Overall, BPN has similar potential for dependence as do methadone and morphine, and a withdrawal state, albeit a milder one, is produced when long-term BPN use is abruptly halted.
This drug can be used as an analgesic, but its use is primarily to stave off withdrawal in those who are already chronic opioid users. In the opioid-dependent individual, BPN can suppress or precipitate withdrawal. It can have either no detectable effects or effects similar to methadone in the non-opioid-dependent subject. BPN can precipitate withdrawal if given to a heroin or methadone addict because of its partial antagonism at the kappa receptor. In clinical use, however, BPN is used to suppress opioid craving and opioid withdrawal (just like methadone). If given to someone who is in active withdrawal, BPN will stop the withdrawal symptoms.
BPN can be used to detox (withdraw) an opioid addict, similar to rapid detox with methadone. Recidivism is high under these circumstances because the craving for opioids is gargantuan, and will return when the short course of BPN is ended. If BPN is given to a methadone maintenance patient, withdrawal will ensue. There are ways to avoid or minimize withdrawal when BPN treatment is initiated in the methadone or heroin addict or when BPN maintenance is substituted for methadone maintenance.
Those maintained on BPN for long periods of time are now BPN-addicted, and they will experience withdrawal once the drug is stopped, but withdrawal symptoms are much milder than seen with heroin or methadone. Withdrawal will occur within several days of abrupt BPN discontinuation.
BPN/Naloxone Combinations: BPN is supplied as a single drug (sublingual tablet) or combined with naloxone. The combination drug (BPN: naloxone in 4:1 ratio) is used in the United States for maintenance therapy. The rationale of combining BPN with naloxone is to limit abuse potential. Because naloxone has little bioavailability from the oral route, this narcotic antagonist is mixed with BPN pills merely to discourage intravenous administration of a crushed tablet. If a combination pill is ground up and injected, the user is giving himself an injection of naloxone, and it precipitates acute withdrawal if he is opioid-dependent. Despite the presence of naloxone, BPN still seems to produce a high when the tablet is injected. When taken orally, the naloxone has no pharmacologic effect, and a similar opioid effect will be felt.
Tolerance: When an individual takes methadone, he quickly becomes tolerant of all opioids, and develops a cross-tolerance with all opioids, including heroin. When used in high doses as maintenance (at least 60 mg), methadone blunts many of the sought-after effects of concurrently administrated heroin, a common activity during relapse in an attempt to get high. Supplemental heroin, therefore, has a minimal effect on the subject taking methadone because the body is tolerant to narcotics. Buying standard doses of heroin on the street becomes a waste of money for the addict maintained on methadone. They can not get high like before, but large doses of heroin will cause opioid toxicity.
BPN exerts effects similar to methadone. Simply stated, methadone and BPN maintenance is effective because the heroin addict does not want to use illegal heroin because he is not in withdrawal, and if he does slip and use heroin or morphine, the effect is minimal because of the extreme tolerance provided by methadone or BPN. In addition, the opioid receptors are essentially blocked by prior BPN administration, and the heroin has no receptor with which to bind. The only downside is that relatively large doses of both BPN and methadone must be used to blunt narcotic cravings and to discourage seeking the supplemental euphoric high.
Duration of Action: Because BPN has a long duration of action (up to 48 to 72 hours depending on dose), there is a slower onset of withdrawal symptoms following discontinuation. Methadone must be given daily, but BPN can be given every two to three days, reducing the number of clinic visits and also reducing the need for take-home medications. Take-home medications always have the potential for illicit diversion, sale on the street, or having a child eat a lost dose. Methadone maintenance requires a daily trip to the methadone clinic, a clear impediment to holding a job, or being otherwise socially or financially productive when one is bound to the clinic’s schedule.
Summary: Overall, BPN has many of the benefits and lacks many of the downsides of methadone maintenance therapy for heroin-addicted patients. BPN could be used to treat oxycodone addicts, probably an even bigger problem but rarely acknowledged. BPN maintenance stops opioid craving and withdrawal, blocks the effect of concurrently administrated opioids through cross-tolerance and receptor blockade, and can be given in a less-than-daily dosing regimen to enhance patient acceptance. And you can get it in the office or drugstore. The occasional paroxysmal pharmacodynamic effect, especially when transferring methadone maintenance patients to BPN maintenance, is a potential downside. The likelihood of IV abuse of the sublingual tablet is somewhat, although apparently not totally, reduced by the combination of naloxone and BPN.
BPN: How to Use it Right
Johnson R, et al
Drug and Alcohol Depend
The authors begin by stating that there are almost a million chronic users of illicit opioids in the United States. If one counts prescription opioids, now much more common than street heroin, this number is much greater. There are two general approaches for treating opioid dependency in the United States. The first is substitute therapy, usually methadone maintenance, and about 200,000 patients receive this type of treatment. Methadone produces a morphine-like milieu in the body, and is simply a substitute for heroin. This makes the patient a methadone addict instead of a morphine and heroin addict.
The obvious downside of opioid addiction intervention is that methadone merely substitutes one addiction for another. Theoretically, this scenario lessens crime, decreases needle-associated infections, reduces accidental overdose, and allows the addict to function in society. Note that heroin is diacetyl morphine, and it is quickly metabolized to morphine in the body. Heroin shows up on a drug test as morphine, and is essentially morphine use.
Another medication for the treatment of opioid dependence is a straightforward antagonist strategy. The medication approved for this is naltrexone. If you take naltrexone (essentially long-acting naloxone), your body and brain will not sense opioids because the receptors are blocked. Unlike methadone, naltrexone does not produce any morphine-like subjective effects. Instead naltrexone is a full opioid antagonist that simply blocks the effect of any administered opioid. Narcotic craving is not blocked by naltrexone. Because patients do not obtain the desired positive subjective effects of narcotics and still yearn for the high, it is difficult to maintain patients on naltrexone therapy. During the more common methadone maintenance approach, the dose of this substituted opioid is increased until opioid craving, additional illicit opioid use, and withdrawal symptoms have abated. This usually requires at least 60 mg of methadone per day, and lower doses often do not suffice. (You have to be high on methadone to resist being high on heroin.)
The benefit of BPN is its high affinity at the mu receptor, and is therefore a bona fide opioid agonist but one with minimal adverse effects. The concomitant kappa receptor antagonist properties of BPN create a desirable safety index relative to respiratory depression while still thwarting opioid withdrawal.
In 2002, the FDA approved BPN and a BPN/naloxone combination for treating opioid dependence. Once an eight-hour training course has been taken, the physician can dispense BPN for opioid addiction in the office. Methadone is only available in specifically licensed methadone maintenance clinics. Although methadone can be prescribed for pain control by any clinician, it cannot be prescribed for opioid dependence unless a special license is granted, with many stipulations and specific recordkeeping required. To repeat, it is illegal for physicians to prescribe methadone without a special license or authorization for opioid addiction outside the boundaries of a methadone maintenance or detoxification center. Such is not the case for BPN.
It is hoped that the office-based system will help remove the opioid dependence stigma, and reduce barriers for treatment. One can get BPN in the office and not have to stand in line with the junkies from the neighborhood. After proving that you are compliant for a few months and do not use additional street drugs, a month’s supply of BPN can be dispensed for home use, something currently not possible with methadone.
BPN maintenance is achieved via sublingual administration. A single 2-4 mg sublingual dose of BPN will attenuate or eliminate signs of opioid withdrawal for about 24 hours in street heroin addicts or in patients abruptly withdrawn from a daily maintenance dose of 60 mg of morphine. Higher doses of BPN are usually prescribed eventually, and will suppress withdrawal for up to 72 hours. At very high doses, BPN can precipitate opioid withdrawal in the opioid-addicted patient, but there is individual susceptibility. BPN has opioid effects on the non-opioid-dependent person, and it has inherent analgesia. Naloxone will reverse all BPN effects, and will precipitate BPN withdrawal in the long-term user, and it is as acceptable as methadone to most street heroin users.
BPN will produce its own physical dependence when given in high doses for long periods of time. But the street heroin or methadone addict is now a respectable office-treated BPN addict. Most patients will be given the combination/naloxone tablet for maintenance, but the single drug is used initially in the addict to lessen withdrawal during induction. One unusual characteristic of BPN is its profile in overdose. Overall, BPN overdose is rather safe and a whole lot safer than methadone overdose. In the event of respiratory depression in overdose, very high doses of naloxone may be required for rescue. BPN sticks stubbornly to the mu receptor. In general, it may take 10-30 mg of naloxone to reverse respiratory depression of BPN. It also lasts longer than naloxone, and once reversal is obtained, further vigilance or observation is required. There are actually very few downsides associated with BPN overdose, and fatalities are quite rare unless there is the all too common concomitant opioid, benzodiazepine, alcohol, or other respiratory depressant use.
When used properly, methadone is a tried and true maintenance medication. It does the job nicely, and is safe when used properly, sometimes a tall order for a heroin addict. Overall, BPN has a better pharmacological profile than methadone for opioid dependence. It has a lower abuse potential, higher safety profile, and excellent clinical flexibility that dwarfs the rather cumbersome use of methadone. In addition, it can be dispensed from an office practice as opposed to a licensed methadone clinic. Cost seems to be the main reason methadone is still more commonly used in this country.
Comment: My personal observation is that opioid addiction is rampant in this country, and an ED shift does not go by without at least two or three patients trying to score narcotics by numerous and often quite ingenious methods. We are all familiar with the guy who brings his MRI with a bulging disc to the ED for proof that he needs narcotics because he is visiting from out of town, the woman whose dog ate the hundred Dilaudid prescribed the day before, or the man whose doctor is on sabbatical in China.
BPN is a relatively new player on the scene. I have seen a few patients on BPN maintenance, and they are not particularly problematic. The sublingual tablet is most commonly used for opioid addiction, and is a Schedule 3 substance. BPN is occasionally used for chronic pain, but it is almost exclusively used for narcotic addiction, primarily in Europe. It has gained popularity in the United States, and emergency physicians should be familiar with it and its quirks.
Some older clinicians may remember the parenteral form, Buprenex, an analgesic that enjoyed minimal popularity. When used for opioid addiction, two formulations are available: Subutex (no additives) and Suboxone (one part naloxone for every four parts BPN). Injected or intranasal Suboxone has decreased effectiveness due to the naloxone component. There is, however, little in the medical literature about this actual effect. I’m not sure how effective it is, and patients still seems to get high. If the naloxone-containing pill is injected intravenously in the addict, it will precipitate acute withdrawal. I have seen a few patients who have scored Suboxone on the street, thinking it was methadone or a similar opioid, and have experienced acute withdrawal when it was injected. The naive user would likely get a high from injecting even the naloxone complex tablet because there is nothing from which to withdraw.
Interestingly, BPN is abused more than cocaine, GHB, or ecstasy in Scandinavian countries, where it has gained great popularity as a street drug. Good news for the drug’s maker and the office practitioner, bad news for the cocaine and ecstasy dealers of Philadelphia. 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. Not to worry, it’s only a matter of time until the U.S. addict catches on. BPN cannot be detected by a urine drug screen. I envision it gaining use for the affluent oxycodone addict who has a private physician to address addiction in a manner more civilized than frequenting the local methadone clinic.
How then will the EP encounter BPN in everyday practice? One case would be the opioid-addicted patient who grinds up and injects a BPN/naloxone tablet, thinking it is similar to methadone. Such patients will experience withdrawal from their chronic opioid addiction. Adding naloxone has done little to discourage street use in Europe. Adding naloxone seems to have no great effect on the sporadic user or weekend opioid neophyte who shoots up the Suboxone pills; it’s still a reasonable high per my sources. A minor withdrawal state may occur if large doses of BPN/naloxone are taken orally. If a child overdoses on BPN, even with naloxone components, respiratory depression and somolence may occur. But do not expect the urine drug screen to be positive for opioids. The clinical pearl here would be that if a patient presents a narcotic toxidrome and is unresponsive to standard doses of naloxone, administering 10 times the normal dose may result in reversal of symptoms if BPN is the culprit.
Next month’s column will address BPN overdose and overall toxicity. I found that Wikipedia has about the best current information on BPN, written in a rather erudite manner.
Opioid receptors are G protein-linked receptors embedded in the plasma membrane of neurons. The mu receptor has the letter m designation because morphine was the first ligand found to bind to it. Activation of the mu receptor by morphine produces analgesia, sedation, itching, nausea, euphoria, respiratory depression, miosis, and decreased bowel motility. Activation of the mu receptor is essential for the rewarding, euphoric, analgesic, and addictive properties of opioids. Significant tolerance can develop to sedation, euphoria, and respiratory depression, but has less analgesia, miosis, and bowel motility.
Overview of Buprenorphine (BPN)
▪ BPN is a partial mu agonist with low intrinsic activity and high receptor affinity.
▪ BPN has minimal kappa receptor antagonism, and its action is derived almost entirely from mu receptor agonism.
▪ Because BPN is a partial mu agonist, its maximum effects will always be lower than that produced by a full mu opioid agonist, such as morphine.
▪ Two formulations are available, and the sublingual tablet containing naloxone is the most commonly used form for addiction maintenance. The pure drug may be used initially to minimize withdrawal in the opioid-addicted patient.
▪ Naloxone is mixed with BPN tablets (1:4 ratio) so IV injection will partially negate opioid properties and produce withdrawal in the opioid-dependent person. The naloxone component has no effect when taken orally, but is intended to discourage IV use of the sublingual tablet.
▪ BPN can be dispensed from an office practice following an eight-hour educational course and certification of the clinician by governmental authority. With proven compliance, BPN may be taken home in a month’s supply.
▪ Very large doses of BPN can cause respiratory depression, especially in the non-tolerant individual. The low intrinsic activity limits respiratory depression, giving BPN a good safety profile.
▪ Concomitant use of benzodiazepines, alcohol, and other respiratory depressants enhances BPN toxicity.
▪ The rare death in overdose is from respiratory depression.
▪ BPN produces characteristic opioid side effects, including constipation, urinary retention, sedation, and miosis.
▪ BPN is not detected by a urine drug screen.
▪ Because the magnitude of euphoric effects is limited, BPN has been associated with a lower abuse potential than methadone. When given to an opioid-dependent subject, BPN can produce withdrawal.
▪ If BPN is given to a patient in opioid withdrawal, symptoms will be suppressed.
▪ BPN discourages illicit narcotic use, decreases disease transmission from dirty needles, can be prescribed in the office to limit the stigma of a methadone clinic, and can allow patients to function well in society.
▪ Chronic BPN administration produces dependency on BPN.
▪ A very large and repeated dose of naloxone may be required to reverse respiratory depression from BPN.
▪ Abrupt discontinuation of BPN will cause a mild to moderate withdrawal syndrome, much less than seen with methadone or heroin.
What is fentanyl?
Fentanyl is a short-acting, synthetic opioid that is 50-100 times more potent than morphine. It is legally
manufactured as a transdermal patch, an oral transmucosal lozenge and as an injection. Abuse of fentanyl
patches is frequently reported. Fentanyl is also illicitly manufactured as a powder and tablets. “Designer”
fentanyl analogs (3-methylfentanyl and alpha-methylfentanyl) are of a higher potency, and have been
implicated in outbreaks of overdoses in several other states in past years.
What are some slang names for fentanyl?
Infamous, flat line, TNT, snow man, THA truth, tsunami and lethal death are some of the slang names that
have been identified for fentanyl. China white often refers to alpha-methylfentanyl. As always, slang names
vary and cannot be relied upon to refer to a particular drug.
DID YOU KNOW THAT
a toxscreen will be negative for opiates when fentanyl has been
Fentanyl is not detected by standard urine opiate immunoassays; therefore, opioid exposures should not be ruled out
based on toxscreen results. To date, the only means of detecting fentanyl in blood or urine is by gas chromatography.
For assistance in diagnosing and managing all opioid overdoses, call the
Maryland Poison Center at 800-222-1222.
Transdermanl Fentanyl in Deliberate Overdose in Pediatrics. Lyttle MD et al. Pediatr Emerg Care 2012;28:463-464.
This case report is annoyingly brief and doesn’t make any new points, but does highlight an important take-home lesson. The case is of a 15-year-old girl found apneic at home after having applied five of her stepfather’s fentanyl patches (100 μg/h each) to her body in a suicide attempt. She required multiple doses of intramuscular and intravenous naloxone to maintain respiratory drive and level of consciousness, and then a naloxone drip for 36 hours after presentation.
Comment from Leon Gussow of TPR:Here’s the tricky part: because fentanyl is so short-acting (duration of IV dose 0.5 – 1.0 hours), it is easy to underestimate how long the effects of transdermal fentanyl will last. However, because of the concentration gradient, when a fentanyl patch is applied a depot of the drug is taken up by skin layers and slowly released into the system. Therefore, even after the patches are removed serum levels can increase, since the elimination half-life is 13 – 22 hours. Patients who experience respiratory depression from fentanyl patches should be observed in a monitored setting for at least 24 hours after patch removal.
b2 adrenergic receptor agonist with a rapid onset and long duration of action approved for limited veterinary use in the United States.2,3 Clenbuterol is also used illicitly as an alternative to anabolic steroids in humans and livestock because it can increase muscle mass.4,5 Most adverse health effects are related to its stimulation of b2 adrenergic receptors and clinical manifestations, including hypokalemia, hyperglycemia, hyperlactemia, agitation, tachycardia, and hypotension.6 Adverse human health effects have been reported previously in a case of clenbuterol ingestion7 and from ingestion of meat from livestock fed clenbuterol.3 However, the 26 cases described in this report are the first published accounts of poisoning from clenbuterol associated with reported heroin use. (JAMA 2005;294(19))
Tramadol / Ultram Overdose
®, Ultracet®) is a centrally-acting analgesic used in the treatment of moderate to severe pain.
It exerts its therapeutic effect via a dual mechanism of action: agonism of mu-opioid receptors and inhibition
of serotonin and norepinephrine reuptake. It reaches peak serum concentrations 2 hours after oral administration
and its elimination half life is 6 hours. While tramadol is an effective analgesic, it is less potent than
other analgesics in its class, e.g. about ten times less potent than codeine. It produces less respiratory depression
and constipation in therapeutic doses than other opioids. Although its abuse potential is unclear,
tramadol should be used cautiously if at all in patients with a history of addiction to opioid analgesics.
Tramadol overdoses are associated with seizures that can occur up to 10 hours post-ingestion. Although not
as common as with other opioids, respiratory depression is seen with overdoses or co-administration with alcohol
or other depressants. Other effects seen in overdoses include lethargy, tachycardia, hypertension, miosis,
nausea, vomiting, constipation, and abdominal pain.
In the treatment of an overdose, activated charcoal can be administered within 1 hour post-ingestion to prevent
absorption. Because of the drugs dual mechanism of action, naloxone will reverse only some of the effects
of tramadol, primarily sedation and respiratory depression. Seizures should be treated with intravenous
The exact amount of tramadol that must be ingested for toxicity to be seen is not known. There have, however,
been cases where ingestions of as little as 500mg of tramadol alone have led to significant symptoms like
seizures and respiratory depression. In any potential overdose, the patient should be observed carefully for
respiratory depression and seizures. It is important to note that since this drug is a synthetic opioid, it will not
show up on a urine drug screen for opiates. Serum concentrations of tramadol can be determined, however,
using high-performance liquid chromatographic methods. maryland toxbits