LETTERS TO THE EDITOR
Access to Alcohol in Hand Sanitizer in a Substance Abuse Treatment Program: A Potentially Overlooked Risk To the Editor: Hospitals and outpatient clinics are generally equipped with alcoholbased hand sanitizers to promote hand hygiene and as a convenient alternative to hand washing. Use of such sanitizers is supported by the Centers for Disease Control and Prevention and the Joint Commission on Accreditation of Healthcare Organizations (Boyce and Pittet, 2002; Joint Commission on Accreditation of Healthcare Organizations, 2007). However, hand sanitizers may provide unintended access to alcohol for patients suffering from alcohol use disorders. We describe intentional ingestion of alcohol-based hand sanitizer by an alcohol dependent patient being treated in an inpatient addiction treatment program.
CASE REPORT A 25-year-old single, unemployed veteran with a history of depression, alcohol use disorder, and posttraumatic stress disorder was brought to the emergency department after he consumed 4 to 5 pints of vodka. The patient seemed intoxicated, with slurred speech, confusion, and unsteady gait. Blood alcohol level was 246 mg/dL; urine toxicology screening was negative. The patient, admitted to the psychiatry service with diagnoses of posttraumatic stress disorder, alcohol use disorder, intoxication, and withdrawal, was treated with intravenous fluids, thiamine, folic acid, glucose, and magnesium in addition to his current psychotropic medications (fluoxetine, quetiapine, and hydroxyzine). Received for publication September 25, 2013; accepted November 16, 2013. The authors declare no conflicts of interest. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0803-0216 DOI: 10.1097/ADM.0000000000000015
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The patient’s condition improved over several days, and he was transferred to the short-term inpatient substance abuse treatment program. On the program, he was noted to repeatedly access hand sanitizer and also had family members bring hand sanitizers during their visits. After one incident of apparent hand sanitizer consumption, the patient’s blood alcohol level was found to be 300 mg/dL. He also reported a history of consuming rubbing (isopropyl) alcohol. The patient was placed on strict observation and restricted from further access to hand sanitizer. After completion of the 30-day inpatient program, he was discharged, with follow-up at his previous psychiatric outpatient clinic.
DISCUSSION The incidence of intentional ingestion of alcohol-containing hand sanitizers has been increasing (Gormley et al., 2012), and hand sanitizer–induced intoxication in inmates and hospitalized patients has been reported (Doyon and Welsh, 2007; Emadi and Coberly, 2007). Liquid hand sanitizer is 60% to 65% ethyl alcohol. Although part of a well-recognized strategy to enhance hand hygiene and prevent spread of pathogens, hand sanitizers can also provide access to alcohol for at-risk patients. Providing patients in “closed” inpatient units with even small amounts of such hand sanitizers for personal use and access to wall placed hand sanitizers intended for medical staff may become clinically problematic for those who suffer from severe alcohol use disorder. Inpatient substance abuse and other clinical programs may wish to consider restricting hand sanitizers to secured staff areas and not permit visitors to bring hand sanitizers onto the unit. On the ward, the location of the containers may best be restricted to areas with public view. Containers of the alcohol-based sanitizers can be secured to require multiple pumps to ingest a large quantity of alcohol, with containers not being removable or able to be opened to extract the entire contents. Foam dispensers of hand cleaners also make it more difficult to obtain large quantities of alcohol. Bactericidal soap and water hand washing is an alter-
native, limited by the architecture of the facility. There is little data supporting the efficacy of nonalcoholic hand sanitizers using quaternary ammonium compounds (ie, benzethonium chloride) to reduce transmission of infection in health care settings, and these are not currently recommended by the Centers for Disease Control and Prevention. The current case underscores the need for high levels of vigilance when treating patients who suffer from alcoholism and the associated highly motivated drug seeking behaviors. It is of note that inactive ingredients in commercially available hand sanitizing gels (isopropyl alcohol, glycerin, carbomer, fragrance, aminomethyl propanol, propylene glycol, isopropyl myristate, and tocopheryl acetate), which make them bitter and unpalatable, seem insufficient to deter consumption by patients such as ours. Although completely removing alcohol-based hand sanitizers from wall dispensers is desirable (Bookstaver et al., 2008), developing technologies that reduce extraction of large quantities may often be more practicable. Mahreen Raza, MD Ankur Patel, MD Steven Schleifer, MD Department of Psychiatry Rutgers New Jersey Medical School Newark, NJ Fouad Eljarrah, MD Addiction Treatment Services VA New Jersey Health Care System East Orange, NJ REFERENCES Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR Recomm Rep 2002;51(RR-16): 1–45. Bookstaver PB, Norris LB, Michaels JE. Ingestion of hand sanitizer by a hospital patient with a history of alcohol abuse. Am J Health Syst Pharm 2008;65:2203. Doyon S, Welsh C. Intoxication of a prison inmate with an ethyl alcohol based hand sanitizer. N Engl J Med 2007;356(5):529–530. Emadi A, Coberly L. Intoxication of a hospitalized patient with an isopropanol-based hand sanitizer. N Engl J Med 2007;356(5):530– 531.
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J Addict Med r Volume 8, Number 3, May/June 2014
Gormley NJ, Bronstein AC, Rasimas JJ, et al. The rising incidence of intentional ingestion of ethanol-containing hand sanitizers. Crit Care Med 2012;40(1):290–294. Joint Commission on Accreditation of Healthcare Organizations. 2007 Comprehensive Accreditation Manual for Hospitals: The Official Handbook (CAMH). Oakbrook Terrace, IL: Joint Commission; 2007.
Another Chance to Reformulate Racemic Methadone To the Editor: Nearly 3 years have passed since I wrote in this journal, suggesting it might be time to reformulate methadone (Karch, 2011). The vast majority of methadone’s narcotic effects are produced by the levo-isomer (pure Risomer), R-(−)-methadone, and nearly all the cardiac arrhythmias are generated by S-(+)-methadone. When I was preparing the 2011 paper, I contacted Covidien Pharmaceuticals, the major manufacturer of methadone in the United States. I asked why they had not already removed S-(+)-methadone, the dangerous component of the drug, from their formulation. Chiral separation of the 2 methadone isomers is a relatively simple process that was first introduced in 1948 (Larsen et al., 1948). This approach to production wastes precious amounts of the chemical-starting material, and leaves behind materials potentially harmful to users, yet it remains the method of choice in Germany even for chiral methadone, which is generated later in the production process. In reply, the manufacturer wrote, “A new drug application (NDA) would need to be submitted to the FDA to approve the formulation as a branded product. This process is accompanied by significant time and cost commitments. Thus, although we cannot enumerate the actual difference in production costs, we Received for publication October 29, 2013; accepted February 26, 2014. Send correspondence and reprint requests to Steven B. Karch, MD, Consultant Pathologist, Berkeley, CA 94708. E-mail: skarch@sonic .net. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0803-0217 DOI: 10.1097/ADM.0000000000000036 C
Another Chance to Reformulate Racemic Methadone
can ascertain that the costs associated with approval of a new branded product would translate to a more significant cost overall for levo-methadone (personal communication).” Covidien never explained why they do not do chiral separation, though they implied it was for financial reasons. Although clinical studies show that the risk of cardiac arrhythmia is real, it is not real enough to cancel out the beneficial effect of methadone being provided both for pain relief and for methadone maintenance treatment (MMT). In 2013, Dutch researchers reported their findings in 130 patients being given methadone for pain. Of the 130 patients studied, they were on average, receiving 18.2 mg/d, 50% were found to be potentially at risk (QT >440 ms) for torsades de pointes and another 5% were clearly at risk with QT intervals 500 ms or more. Thus, the potential for bad outcome, though small, is real even at lower dosage (van den Beukenvan Everdingen et al., 2013), and careful monitoring of dosage and time of administration is essential. Further examples are given by other recent studies with regard to dosage and QTc values (Reddy et al., 2004; Fonseca et al., 2009; Roy et al., 2012). Even before I submitted my editorial, methadone-related deaths had begun to explode within the United States. Six times as many people died of methadone overdoses in 2009 than a decade earlier (Fig. 1). In 2012, almost one third of all prescription painkiller overdose deaths involved methadone. More precisely, the Centers for Disease Control (CDC) reported that 15,500 Americans die every year of prescription drug overdose, and that nearly one third of those overdoses involve methadone (Centers for Disease Control and Prevention, 2012; Paulozzi et al., 2012). Methadone accounts for only 2% of all painkiller prescriptions in the United States, but it is involved in more than 30% of prescription painkiller overdose deaths. Medical examiner data suggest that more than 3 quarters of methadone overdoses involved persons who were not enrolled in MMT programs—they were using methadone without a prescription or were receiving prescribed
methadone for pain, not addiction treatment. In 2013, writing in the Annals of Internal Medicine, Kao et al. reported findings from the national adverse event registry. The review covered the period just before publication of a 2002 report describing an association between methadone and arrhythmia. It described the rate for methadone arrhythmias then and now (Kao et al., 2013). The statistical significance of their findings was indisputable. Of 1646 methadone-related cases of ventricular arrhythmia or cardiac arrest, there were 379 cases of QTc prolongation or torsade de pointes. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1–0.5), before the 2002 publication of the index paper, to a mean of 3.5 cases (CI, 2.5–4.8) after it. In 2012, the CDC reported that in the United States, both the number of methadone overdose deaths and the quantity of methadone sold peaked in 2007. In 2010, it was reported that, depending on the state, methadone accounted for between 4.5% and 18.5% of the opioids sold, and was involved in 31.4% of opioid pain reliever (OPR) deaths in 13 US states. Methadone accounted for even more single drug deaths (39.8%) than other OPR drugs. The percentage of methadone involvement was much greater in polypharmacy deaths than in clinical application, suggesting, again, it is drug abuse, not MMT, which accounts for the excess deaths associated with pain relief applications. Clearly, methadone itself has not become more toxic. Before the explosion in methadone-related deaths the only individuals taking methadone were heroin addicts seeking to minimize the harm of their own addiction, or better still, discontinue use of the drug altogether. But, as the Director of the CDC told Time Magazine, “All of the evidence suggests that the increase in methadone related deaths is related to increased use of methadone to treat pain (Szalavitz, 2012),” few dispute this assessment. Methadone has been used safely to treat heroin addiction since the 1960s, but in recent years it has become a frontline pain medication. In November 2006, federal health officials
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FIGURE 1. The rate of overdose deaths involving methadone in the United State in 2009 was 5.5 times the rate in 1999. The mortality rate peaked at 1.8 deaths per 100,000 persons. Methadone accounted for 4.4 million (1.7%) of the 257 mg of morphine equivalents sold in 2010. (Reprinted with permission from Paulozzi et al. 2012).
warned against using methadone as a first-choice pain reliever and added a “black box warning” to the package insert; but the warning has not been effective and the death rate continues to rise. As the CDC has observed, when the rate of nonmedical methadone use rises, so does the number of fatal overdoses. The drugs involved in these cases are typically diverted from the pain treatment community, and most certainly not from addiction treatment programs. In Germany, both the racemic and pure levo-isomers are available to patients with MMT, and doctors may prescribe whichever they wish (making appropriate adjustments for the increased potency of the pure isomer). The levoisomer is produced by Sanofi Aventis, an international pharmaceutical manufacturer, in one of its German facilities, under the name L-Polamidon. Germany, a country known for its highly effective pharmacovigilance system, monitors use of this compound. Yet, despite the availability of the levo-isomer, German MMT programs have not reported any significant problems either to the government or in the peer-reviewed literature. Nor were any problems reported in the 1990s when the levo-isomer was the only type of methadone allowed for use in MMT programs. On May 24, 2013, Covidien announced that it was spinning off its pharmaceutical business to Mallinck-
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though the Food and Drug Administration (FDA) has tried to simplify the licensing process (Nadler and de GraftHohnson, 2009), there is no getting round the issue that the US government will require proof that removing a potential toxic agent, from a widely used racemic formulation already in use, will require further proof that the new, improved, product is safe. A precedent in October 2013 was recently set with the approval of Fetzima, the active enantiomer of the previously approved racemate milnacipran HCl. The justification was FDC Act s.505(u). This act allows a racemate switch and gives 5 years of exclusivity to new chemical entity. It seems unlikely that the FDA will accept European evidence, though it is difficult to think of a reason why not because for many years R-(−)-methadone was the only methadone available in Germany. Even if one were to attempt a cost analysis (let alone attempt to estimate the number of lives saved), there would be no way to verify the results of a comparison study. The process of introducing a new drug is arcane art, practiced by drug makers and regulators, not clinicians. Drug makers claim the cost is in the billions, but fail to mention the costs they quote also include developing the drug in the first place (Werth, 2013). Others disagree strongly. It is always difficult trying to decide which vested interest to believe (Silverman,
rodt. Given the new corporate structure, now might be a very good time to renew pressure for reformulation. Several developments make this seem like a realistic possibility. The first is a new development in the manufacturing process. Ten years ago, a method for asymmetric chiral methadone synthesis was devised. It uses cheap chiral-starting materials, and results in the production of both levo- and dextro-isomers by asymmetric synthesis (Hull et al., 2003). But it has not been adopted because of the costs associated with the requirements of the regulatory authorities. A patent has been granted on this new asymmetric synthetic process (U.S.P. 6143933), and the production cost would likely be much less today than using the traditional method. Even so, the cost of the pure levo-isomer, produced using traditional methods, does not seem to be very great. The final cost per dose of the pure levo-isomer produced by the new asymmetric synthesis is not known. However, methadone is a relatively inexpensive drug, and multiplying its cost by a factor of 2 to 3 is unlikely to affect affordability (Swissinfo.com, 2007). Any attempt to introduce a new method of methadone production, even if the final product was far safer than the current product, would certainly meet great resistance from both the US government and the manufacturers. Even C
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2011). This is why it might be a very good time for the treatment community to make its wishes known, not to just Mallinckrodt and Sanofi, but to the FDA as well. Neither entity should lose sight that, after all, we are talking about easily preventable deaths, and that there are more than a few generic drug makers who would be happy to make the safe product if they could get a license. The time to act is now. There is one final caveat. Even the pure R-isomer of methadone is a dangerous drug in the hands of the wrong practitioners, especially those who have not been trained in its proper use. Tolerance to methadone is slow to develop and quick to dissipate. Most of the deaths in MMT programs occur during the initiation of therapy, apparently because the dose is increased too quickly to allow tolerance to occur (Drummer et al., 1992). Loss of tolerance poses an equally large problem (Harding-Pink and Fryc, 1988). To date, methadone dosing is still an issue of debate and personal preference (Fareed et al., 2010), and lower dosage can be achieved by using the optically active isomer R-(−)methadone. The simple truth is that factors associated with opioid tolerance have not been well studied in human patients. Determining which individual and which treatment delivery variables are associated with increased methadone will require real-life clinical samples. Once that information becomes available, it will eventually be possible to rationalize
C
Another Chance to Reformulate Racemic Methadone
the therapeutic use of opioids (Trafton et al., 2006). Both the UK and US governments recommend twice a day dosing (the current US package insert recommends a starting dose of 2.5–10 mg every 8–12 hours) (Fareed et al., 2010). All of these issues will need to be reconsidered if a new form of methadone, R-(–)-methadone, ever comes to market. Steven B. Karch, MD Consultant Pathologist, Berkeley, CA REFERENCES Centers for Disease Control and Prevention. CDC Vital Signs: Prescription Painkiller Overdoses. July 2012. http://www.cdc.gov/ vitalSigns/MethadoneOverdoses/index.html. Updated July 3, 2012. Accessed April 1, 2014. Drummer OH, Opeskin K, Syrjanen M, et al. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol 1992;13(4):346–350. Fareed A, Casarella J, Amar R, et al. Methadone maintenance dosing guideline for opioid dependence, a literature review. J Addict Dis 2010;29(1):1–14. Fonseca F, Marti-Almor J, Pastor A, et al. Prevalence of long QTc interval in methadone maintenance patients. Drug Alcohol Depend 2009;99(1–3):327–332. Harding-Pink D, Fryc O. Risk of death after release from prison: a duty to warn. BMJ 1988;297(6648):596. Hull J, Scheinmann F, Turner NJ. Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations. Tetrahedron Asymmetr 2003;14:567–576. Kao D, Bucher Bartelson B, Khatri V, et al. Trends in reporting methadone-associated cardiac arrhythmia, 1997–2011: an analysis of registry data. Ann Intern Med 2013;158(10): 735–740.
Karch SB. Is it time to reformulate racemic methadone? J Addict Med 2011;5(3): 229–231. Larsen AA, Tullar BF, Elpern B, et al. The resolution of methadone and related compounds. J Am Chem Soc 1948;70(12):4194–4197. Nadler HL, de Graft-Johnson D. Demystifying FDA’s 505(B)(2) Drug Registration Process. Regul Focus 2009;1–7. Paulozzi LJ, Mack KA, Jones CM. Centers for Disease Control and Prevention (CDC). Vital signs: Risk for overdose from methadone used for pain relief - United States, 19992010. MMWR Morb Mortal Wkly Rep 2012; Jul 6;61(26):493–497. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. J Pain Symptom Manage 2004;28(4):301–303. Roy AK, McCarthy C, Kiernan G, et al. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction 2012;107(6):1132–1139. Silverman D. FDA approvals of old drugs put new pressure on payers. Manag Care 2011;20(5):30–31. Swissinfo.ch. Scientists get a fix on methadone costs. March 6, 2007. Available at http://www .swissinfo.ch/eng/Home/Archive/Scientists_get_ a_fix_on_methadone_risks.html?cid=5762666. Accessed January 22, 2014. Szalavitz M. Methadone: A Major Driver of Prescription Painkiller Overdose Deaths. Time Magazine Online, 2012. Trafton JA, Minkel J, Humphreys K. Determining effective methadone doses for individual opioid-dependent patients. PLoS Med 2006;3(3):e80. van den Beuken-van Everdingen MH, Geurts JW, Patijn J. Prolonged QT interval by methadone: relevance for daily practice? A prospective study in patients with cancer and noncancer pain. J Opioid Manag 2013;9(4): 263–267. Werth B. A Tale of Two Drugs. MIT Technology Review Magazine, 2013.
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Access to Alcohol in Hand Sanitizer in a Substance Abuse Treatment Program: A Potentially Overlooked Risk To the Editor: Hospitals and outpatient clinics are generally equipped with alcoholbased hand sanitizers to promote hand hygiene and as a convenient alternative to hand washing. Use of such sanitizers is supported by the Centers for Disease Control and Prevention and the Joint Commission on Accreditation of Healthcare Organizations (Boyce and Pittet, 2002; Joint Commission on Accreditation of Healthcare Organizations, 2007). However, hand sanitizers may provide unintended access to alcohol for patients suffering from alcohol use disorders. We describe intentional ingestion of alcohol-based hand sanitizer by an alcohol dependent patient being treated in an inpatient addiction treatment program.
CASE REPORT A 25-year-old single, unemployed veteran with a history of depression, alcohol use disorder, and posttraumatic stress disorder was brought to the emergency department after he consumed 4 to 5 pints of vodka. The patient seemed intoxicated, with slurred speech, confusion, and unsteady gait. Blood alcohol level was 246 mg/dL; urine toxicology screening was negative. The patient, admitted to the psychiatry service with diagnoses of posttraumatic stress disorder, alcohol use disorder, intoxication, and withdrawal, was treated with intravenous fluids, thiamine, folic acid, glucose, and magnesium in addition to his current psychotropic medications (fluoxetine, quetiapine, and hydroxyzine). Received for publication September 25, 2013; accepted November 16, 2013. The authors declare no conflicts of interest. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0803-0216 DOI: 10.1097/ADM.0000000000000015
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The patient’s condition improved over several days, and he was transferred to the short-term inpatient substance abuse treatment program. On the program, he was noted to repeatedly access hand sanitizer and also had family members bring hand sanitizers during their visits. After one incident of apparent hand sanitizer consumption, the patient’s blood alcohol level was found to be 300 mg/dL. He also reported a history of consuming rubbing (isopropyl) alcohol. The patient was placed on strict observation and restricted from further access to hand sanitizer. After completion of the 30-day inpatient program, he was discharged, with follow-up at his previous psychiatric outpatient clinic.
DISCUSSION The incidence of intentional ingestion of alcohol-containing hand sanitizers has been increasing (Gormley et al., 2012), and hand sanitizer–induced intoxication in inmates and hospitalized patients has been reported (Doyon and Welsh, 2007; Emadi and Coberly, 2007). Liquid hand sanitizer is 60% to 65% ethyl alcohol. Although part of a well-recognized strategy to enhance hand hygiene and prevent spread of pathogens, hand sanitizers can also provide access to alcohol for at-risk patients. Providing patients in “closed” inpatient units with even small amounts of such hand sanitizers for personal use and access to wall placed hand sanitizers intended for medical staff may become clinically problematic for those who suffer from severe alcohol use disorder. Inpatient substance abuse and other clinical programs may wish to consider restricting hand sanitizers to secured staff areas and not permit visitors to bring hand sanitizers onto the unit. On the ward, the location of the containers may best be restricted to areas with public view. Containers of the alcohol-based sanitizers can be secured to require multiple pumps to ingest a large quantity of alcohol, with containers not being removable or able to be opened to extract the entire contents. Foam dispensers of hand cleaners also make it more difficult to obtain large quantities of alcohol. Bactericidal soap and water hand washing is an alter-
native, limited by the architecture of the facility. There is little data supporting the efficacy of nonalcoholic hand sanitizers using quaternary ammonium compounds (ie, benzethonium chloride) to reduce transmission of infection in health care settings, and these are not currently recommended by the Centers for Disease Control and Prevention. The current case underscores the need for high levels of vigilance when treating patients who suffer from alcoholism and the associated highly motivated drug seeking behaviors. It is of note that inactive ingredients in commercially available hand sanitizing gels (isopropyl alcohol, glycerin, carbomer, fragrance, aminomethyl propanol, propylene glycol, isopropyl myristate, and tocopheryl acetate), which make them bitter and unpalatable, seem insufficient to deter consumption by patients such as ours. Although completely removing alcohol-based hand sanitizers from wall dispensers is desirable (Bookstaver et al., 2008), developing technologies that reduce extraction of large quantities may often be more practicable. Mahreen Raza, MD Ankur Patel, MD Steven Schleifer, MD Department of Psychiatry Rutgers New Jersey Medical School Newark, NJ Fouad Eljarrah, MD Addiction Treatment Services VA New Jersey Health Care System East Orange, NJ REFERENCES Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR Recomm Rep 2002;51(RR-16): 1–45. Bookstaver PB, Norris LB, Michaels JE. Ingestion of hand sanitizer by a hospital patient with a history of alcohol abuse. Am J Health Syst Pharm 2008;65:2203. Doyon S, Welsh C. Intoxication of a prison inmate with an ethyl alcohol based hand sanitizer. N Engl J Med 2007;356(5):529–530. Emadi A, Coberly L. Intoxication of a hospitalized patient with an isopropanol-based hand sanitizer. N Engl J Med 2007;356(5):530– 531.
J Addict Med r Volume 8, Number 3, May/June 2014
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J Addict Med r Volume 8, Number 3, May/June 2014
Gormley NJ, Bronstein AC, Rasimas JJ, et al. The rising incidence of intentional ingestion of ethanol-containing hand sanitizers. Crit Care Med 2012;40(1):290–294. Joint Commission on Accreditation of Healthcare Organizations. 2007 Comprehensive Accreditation Manual for Hospitals: The Official Handbook (CAMH). Oakbrook Terrace, IL: Joint Commission; 2007.
Another Chance to Reformulate Racemic Methadone To the Editor: Nearly 3 years have passed since I wrote in this journal, suggesting it might be time to reformulate methadone (Karch, 2011). The vast majority of methadone’s narcotic effects are produced by the levo-isomer (pure Risomer), R-(−)-methadone, and nearly all the cardiac arrhythmias are generated by S-(+)-methadone. When I was preparing the 2011 paper, I contacted Covidien Pharmaceuticals, the major manufacturer of methadone in the United States. I asked why they had not already removed S-(+)-methadone, the dangerous component of the drug, from their formulation. Chiral separation of the 2 methadone isomers is a relatively simple process that was first introduced in 1948 (Larsen et al., 1948). This approach to production wastes precious amounts of the chemical-starting material, and leaves behind materials potentially harmful to users, yet it remains the method of choice in Germany even for chiral methadone, which is generated later in the production process. In reply, the manufacturer wrote, “A new drug application (NDA) would need to be submitted to the FDA to approve the formulation as a branded product. This process is accompanied by significant time and cost commitments. Thus, although we cannot enumerate the actual difference in production costs, we Received for publication October 29, 2013; accepted February 26, 2014. Send correspondence and reprint requests to Steven B. Karch, MD, Consultant Pathologist, Berkeley, CA 94708. E-mail: skarch@sonic .net. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0803-0217 DOI: 10.1097/ADM.0000000000000036 C
Another Chance to Reformulate Racemic Methadone
can ascertain that the costs associated with approval of a new branded product would translate to a more significant cost overall for levo-methadone (personal communication).” Covidien never explained why they do not do chiral separation, though they implied it was for financial reasons. Although clinical studies show that the risk of cardiac arrhythmia is real, it is not real enough to cancel out the beneficial effect of methadone being provided both for pain relief and for methadone maintenance treatment (MMT). In 2013, Dutch researchers reported their findings in 130 patients being given methadone for pain. Of the 130 patients studied, they were on average, receiving 18.2 mg/d, 50% were found to be potentially at risk (QT >440 ms) for torsades de pointes and another 5% were clearly at risk with QT intervals 500 ms or more. Thus, the potential for bad outcome, though small, is real even at lower dosage (van den Beukenvan Everdingen et al., 2013), and careful monitoring of dosage and time of administration is essential. Further examples are given by other recent studies with regard to dosage and QTc values (Reddy et al., 2004; Fonseca et al., 2009; Roy et al., 2012). Even before I submitted my editorial, methadone-related deaths had begun to explode within the United States. Six times as many people died of methadone overdoses in 2009 than a decade earlier (Fig. 1). In 2012, almost one third of all prescription painkiller overdose deaths involved methadone. More precisely, the Centers for Disease Control (CDC) reported that 15,500 Americans die every year of prescription drug overdose, and that nearly one third of those overdoses involve methadone (Centers for Disease Control and Prevention, 2012; Paulozzi et al., 2012). Methadone accounts for only 2% of all painkiller prescriptions in the United States, but it is involved in more than 30% of prescription painkiller overdose deaths. Medical examiner data suggest that more than 3 quarters of methadone overdoses involved persons who were not enrolled in MMT programs—they were using methadone without a prescription or were receiving prescribed
methadone for pain, not addiction treatment. In 2013, writing in the Annals of Internal Medicine, Kao et al. reported findings from the national adverse event registry. The review covered the period just before publication of a 2002 report describing an association between methadone and arrhythmia. It described the rate for methadone arrhythmias then and now (Kao et al., 2013). The statistical significance of their findings was indisputable. Of 1646 methadone-related cases of ventricular arrhythmia or cardiac arrest, there were 379 cases of QTc prolongation or torsade de pointes. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1–0.5), before the 2002 publication of the index paper, to a mean of 3.5 cases (CI, 2.5–4.8) after it. In 2012, the CDC reported that in the United States, both the number of methadone overdose deaths and the quantity of methadone sold peaked in 2007. In 2010, it was reported that, depending on the state, methadone accounted for between 4.5% and 18.5% of the opioids sold, and was involved in 31.4% of opioid pain reliever (OPR) deaths in 13 US states. Methadone accounted for even more single drug deaths (39.8%) than other OPR drugs. The percentage of methadone involvement was much greater in polypharmacy deaths than in clinical application, suggesting, again, it is drug abuse, not MMT, which accounts for the excess deaths associated with pain relief applications. Clearly, methadone itself has not become more toxic. Before the explosion in methadone-related deaths the only individuals taking methadone were heroin addicts seeking to minimize the harm of their own addiction, or better still, discontinue use of the drug altogether. But, as the Director of the CDC told Time Magazine, “All of the evidence suggests that the increase in methadone related deaths is related to increased use of methadone to treat pain (Szalavitz, 2012),” few dispute this assessment. Methadone has been used safely to treat heroin addiction since the 1960s, but in recent years it has become a frontline pain medication. In November 2006, federal health officials
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FIGURE 1. The rate of overdose deaths involving methadone in the United State in 2009 was 5.5 times the rate in 1999. The mortality rate peaked at 1.8 deaths per 100,000 persons. Methadone accounted for 4.4 million (1.7%) of the 257 mg of morphine equivalents sold in 2010. (Reprinted with permission from Paulozzi et al. 2012).
warned against using methadone as a first-choice pain reliever and added a “black box warning” to the package insert; but the warning has not been effective and the death rate continues to rise. As the CDC has observed, when the rate of nonmedical methadone use rises, so does the number of fatal overdoses. The drugs involved in these cases are typically diverted from the pain treatment community, and most certainly not from addiction treatment programs. In Germany, both the racemic and pure levo-isomers are available to patients with MMT, and doctors may prescribe whichever they wish (making appropriate adjustments for the increased potency of the pure isomer). The levoisomer is produced by Sanofi Aventis, an international pharmaceutical manufacturer, in one of its German facilities, under the name L-Polamidon. Germany, a country known for its highly effective pharmacovigilance system, monitors use of this compound. Yet, despite the availability of the levo-isomer, German MMT programs have not reported any significant problems either to the government or in the peer-reviewed literature. Nor were any problems reported in the 1990s when the levo-isomer was the only type of methadone allowed for use in MMT programs. On May 24, 2013, Covidien announced that it was spinning off its pharmaceutical business to Mallinck-
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though the Food and Drug Administration (FDA) has tried to simplify the licensing process (Nadler and de GraftHohnson, 2009), there is no getting round the issue that the US government will require proof that removing a potential toxic agent, from a widely used racemic formulation already in use, will require further proof that the new, improved, product is safe. A precedent in October 2013 was recently set with the approval of Fetzima, the active enantiomer of the previously approved racemate milnacipran HCl. The justification was FDC Act s.505(u). This act allows a racemate switch and gives 5 years of exclusivity to new chemical entity. It seems unlikely that the FDA will accept European evidence, though it is difficult to think of a reason why not because for many years R-(−)-methadone was the only methadone available in Germany. Even if one were to attempt a cost analysis (let alone attempt to estimate the number of lives saved), there would be no way to verify the results of a comparison study. The process of introducing a new drug is arcane art, practiced by drug makers and regulators, not clinicians. Drug makers claim the cost is in the billions, but fail to mention the costs they quote also include developing the drug in the first place (Werth, 2013). Others disagree strongly. It is always difficult trying to decide which vested interest to believe (Silverman,
rodt. Given the new corporate structure, now might be a very good time to renew pressure for reformulation. Several developments make this seem like a realistic possibility. The first is a new development in the manufacturing process. Ten years ago, a method for asymmetric chiral methadone synthesis was devised. It uses cheap chiral-starting materials, and results in the production of both levo- and dextro-isomers by asymmetric synthesis (Hull et al., 2003). But it has not been adopted because of the costs associated with the requirements of the regulatory authorities. A patent has been granted on this new asymmetric synthetic process (U.S.P. 6143933), and the production cost would likely be much less today than using the traditional method. Even so, the cost of the pure levo-isomer, produced using traditional methods, does not seem to be very great. The final cost per dose of the pure levo-isomer produced by the new asymmetric synthesis is not known. However, methadone is a relatively inexpensive drug, and multiplying its cost by a factor of 2 to 3 is unlikely to affect affordability (Swissinfo.com, 2007). Any attempt to introduce a new method of methadone production, even if the final product was far safer than the current product, would certainly meet great resistance from both the US government and the manufacturers. Even C
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J Addict Med r Volume 8, Number 3, May/June 2014
2011). This is why it might be a very good time for the treatment community to make its wishes known, not to just Mallinckrodt and Sanofi, but to the FDA as well. Neither entity should lose sight that, after all, we are talking about easily preventable deaths, and that there are more than a few generic drug makers who would be happy to make the safe product if they could get a license. The time to act is now. There is one final caveat. Even the pure R-isomer of methadone is a dangerous drug in the hands of the wrong practitioners, especially those who have not been trained in its proper use. Tolerance to methadone is slow to develop and quick to dissipate. Most of the deaths in MMT programs occur during the initiation of therapy, apparently because the dose is increased too quickly to allow tolerance to occur (Drummer et al., 1992). Loss of tolerance poses an equally large problem (Harding-Pink and Fryc, 1988). To date, methadone dosing is still an issue of debate and personal preference (Fareed et al., 2010), and lower dosage can be achieved by using the optically active isomer R-(−)methadone. The simple truth is that factors associated with opioid tolerance have not been well studied in human patients. Determining which individual and which treatment delivery variables are associated with increased methadone will require real-life clinical samples. Once that information becomes available, it will eventually be possible to rationalize
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Another Chance to Reformulate Racemic Methadone
the therapeutic use of opioids (Trafton et al., 2006). Both the UK and US governments recommend twice a day dosing (the current US package insert recommends a starting dose of 2.5–10 mg every 8–12 hours) (Fareed et al., 2010). All of these issues will need to be reconsidered if a new form of methadone, R-(–)-methadone, ever comes to market. Steven B. Karch, MD Consultant Pathologist, Berkeley, CA REFERENCES Centers for Disease Control and Prevention. CDC Vital Signs: Prescription Painkiller Overdoses. July 2012. http://www.cdc.gov/ vitalSigns/MethadoneOverdoses/index.html. Updated July 3, 2012. Accessed April 1, 2014. Drummer OH, Opeskin K, Syrjanen M, et al. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol 1992;13(4):346–350. Fareed A, Casarella J, Amar R, et al. Methadone maintenance dosing guideline for opioid dependence, a literature review. J Addict Dis 2010;29(1):1–14. Fonseca F, Marti-Almor J, Pastor A, et al. Prevalence of long QTc interval in methadone maintenance patients. Drug Alcohol Depend 2009;99(1–3):327–332. Harding-Pink D, Fryc O. Risk of death after release from prison: a duty to warn. BMJ 1988;297(6648):596. Hull J, Scheinmann F, Turner NJ. Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations. Tetrahedron Asymmetr 2003;14:567–576. Kao D, Bucher Bartelson B, Khatri V, et al. Trends in reporting methadone-associated cardiac arrhythmia, 1997–2011: an analysis of registry data. Ann Intern Med 2013;158(10): 735–740.
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