Painkillers Linked to Increase in Overdose Deaths. More popularity, availability of these medications may be reason, study suggests.

Steven Reinberg HealthDay News, December 9, 2008 TUESDAY, Dec. 9 (HealthDay News) -- Deaths from overdoses of prescription drugs, primarily pain relievers, appear to be on the rise throughout the United States, new research suggests. West Virginia, in particular, has seen a large increase in such unintentional deaths, say government researchers, who have uncovered patterns of "doctor shopping" for drugs and overdosing on medications not used as prescribed. "We found that two-thirds of these deaths involved prescription drugs that had not been prescribed to the individuals who died," said the lead researcher, Dr. Aron J. Hall, an epidemic intelligence service officer for the U.S. Centers for Disease Control and Prevention. In addition, one in five had "doctor shopped," looking for physicians to prescribe pain medications, particularly opioids like methadone, hydrocodone and oxycodone, Hall said. "This epidemic of prescription drug overdose involves a substantial amount of substance abuse, and it affects not just West Virginia, but particularly rural areas of the country," Hall said. "It's been a problem throughout the country. Our study focused on West Virginia as the tip of the iceberg." Hall's group thinks that doctors and pharmacists have a critical role in preventing the misuse of these drugs. "It is essential that they counsel patients not only about the risk of overdose to themselves, but about the risks to those with whom they might share their drugs," he said. In addition, Hall advises doctors to use prescription monitoring programs, which can tell them if patients are getting drugs from other doctors. The report is published in the Dec. 10 issue of the Journal of the American Medical Association. For the study, Hall's team looked at deaths from unintentional overdoses in West Virginia in 2006. From 1999 to 2004, deaths from unintentional poisoning in the state increased 550 percent, the greatest increase for any state in the country. To determine the size of the problem in West Virginia, the researchers collected data from medical examiners, prescription drug-monitoring programs, and opiate treatment program records. In 2006, 295 West Virginians died from unintentional overdoses of pain killers, Hall's group found. Of these, 67.1 percent were men and 91.9 percent were between the ages of 18 and 54. Most on those who died (63.1 percent) used painkillers, but did not have a prescription for them. And 21.5 percent had prescriptions for these drugs from at least five doctors in the year before their death, the researchers found. Women were more likely to doctor shop than men (30.9 percent vs. 16.7 percent), and younger people used painkillers for non-medical purposes more than their older counterparts did, according to the report. In 79.3 percent of the deaths, people had used several medications. Opioids were the most common drugs used, accounting for 93.2 percent of the deaths. Of these deaths, only 44.4 percent of the victims had any evidence of having a prescription for these drugs, Hall's group noted. Methadone was the most common drug linked to fatal overdoses, accounting for 40 percent of the deaths. People who died from a methadone overdose were less likely to have a prescription for the drug than people who overdosed on hydrocodone or oxycodone, the researchers found. In 1997, two reports called for better management of chronic pain and encouraged the use of opioid pain medications. Since that time, the sales of these painkillers has gone up dramatically as have overdoses, deaths and recreational use linked to these drugs, Hall said. Dr. Adam Bisaga, an associate professor of clinical psychiatry in the division on substance abuse at Columbia University College of Physicians and Surgeons in New York City, thinks that improved guidelines for appropriate prescribing, along with training to detect substance use disorders in patients, might reduce the unintended consequences seen in this study. "This finding is not surprising. Opiates are generally very safe if used appropriately, but opiate abuse/dependence is an illness with high mortality rates," Bisaga said. "So the issue is not with the medication, but rather the detection and treatment of those who abuse and become addicted to opiates." In addition, there is a need to expand access to addiction treatment, particularly in high-risk populations, Bisaga said. "I strongly believe that present results could be directly used to justify implementing changes in practice and treatment to promptly reverse this worrisome trend that is likely to be occurring throughout the country, not just in one state," Bisaga said. More information For more on prescription drug abuse, visit the U.S. National Institute on Drug Abuse. Link to Article.

A Literature Search of QT Related Tachycardia in Methadone Maintenance Patients

Comments by Andrew Byrne
Surgery web page: http://www.redfernclinic.com/#news

Publication: Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D,  2006. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction 101: 1333-1338.

The Addiction journal has a literature search of torsade arrhythmias in methadone maintenance patients.  In 14 published reports, Dr Justo and colleagues found 40 documented cases, excluding those treated for chronic pain. 

The median age was 41 years and 68% were male.  The mean daily dose was 231mg.  The corrected QT interval (QTc) around the time of the arrhythmia was 598 ± 75ms (~normal <450 male, <470 female).  All patients reportedly survived the torsade episode(s). 

In analysing the individual case reports, the authors found that 85% of subjects had one or more additional contributing factors over and above the use of methadone (mostly at very high doses).  These factors included 22 patients (55%) taking drugs known to cause QT prolongation or to increase methadone levels; 16 (40%) with HIV infection; 14 (35%) had hypokalaemia; 11 (28%) had cirrhosis or renal failure and 9 (23%) had heart disease.   Many had two or more of these additional risk factors.  There were two cases of familial long QT syndrome, both women. 

Justo and colleagues conclude that methadone may join a pharmacological category like amiodarone which causes significant QT prolongation but which is only rarely associated with torsades. 

Erich Wedam’s RCT report (2007) and Janet Lipsky (1973) attest to frequent QTc prolongation in early methadone patients (23% and 34%).  Yet no cases of torsades were reported and indeed tachycardia is either extremely rare or non-existent in such patients who form a quite different group to the torsade cases summarised in Addiction. 

This is very reassuring information showing that the torsade arrhythmia does not seem to happen without warning in our usual patient group.  Almost every case reported in the world literature was taking very high doses (in Krantz’s series it was 400mg daily) as well as usually also having one or more serious risk factors such as older age, HIV, co-medication, organ failure or heart disease.  All of these are easy to recognise as long as the patients have regular and comprehensive medical assessments (including a cardiograph in appropriate cases).  Personal or family history of syncope would be essential information. 

According to Krantz’s experience in the field, the opioid treatment setting is an ideal venue for cardiac monitoring and preventive health strategies such as lipid studies, dietary advice, blood pressure, smoking cessation and harm reduction education which may help avoid infections including endocarditis (see ref below).  Such attention to clinical detail will become even more relevant as our patients get older and as Krantz also points out, as maintenance treatments are used more in the community.  He also mentions some tantalizing but as yet unproven information that there may be less coronary artery disease in those on long term opioids (also see Marmor, Maslansky et al). 

It is hard to know how much attention front-line clinicians have been paying to the QT issue but one hopes that it does not detract from crucial issues such as treatment access and effectiveness. 

References:

Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124: 2940–1   http://www.unboundmedicine.com/medline/ebm/record/15550974/abstract/.

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473.

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml.

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004 93:1295-1297.

Amiodarone Review: http://www.eboncall.org/CATs/2611.htm.

Methadone Maintenance 4 Decades Later

JAMA. 2008;300(19):2303-2305.

Methadone Maintenance 4 Decades Later

Thousands of Lives Saved But Still Controversial

Commentary by Herbert D. Kleber, MD

SUMMARY OF THE ORIGINAL ARTICLE

A Medical Treatment for Diacetylmorphine (Heroin) Addiction:
A Clinical Trial With Methadone Hydrochloride
Vincent P. Dole, MD, and Marie Nyswander, MD

JAMA. 1965;193(8):646-650.

Twenty-two male patients, addicted to heroin 9.5 years (median), were stabilized using oral methadone hydrochloride and then observed for approximately 1 to 15 months (median, 3 months). The medication had 2 main effects: (1) relief of narcotic hunger (craving); and (2) induction of sufficient tolerance to block the average illegal dose of heroin.

A combination of the methadone treatment and a comprehensive program of rehabilitation was associated with marked improvement in patient problems such as jobs, returning to school, and family reconciliation. No adverse effect other than constipation was found.

The authors note that "careful medical supervision and many social services" were necessary and stressed that "both the medication and supporting program were essential." The small size of the group studied and short duration of the follow-up would best describe this as a promising and exciting but preliminary report.

See PDF for full text of the original JAMA article.

Commentary

The effects of the article by Dole and Nyswander¹ are best understood by knowing what preceded it. The current scientific consensus is that opioid dependence is a chronic and severe medical disorder, and withdrawal alone is usually followed by rapid relapse.² A century ago, however, withdrawal was often considered adequate to treat narcotic addiction, with methods used often more dangerous than withdrawal. Individuals who relapsed were viewed as doing so out of choice rather than necessity.

The frequency of relapse, however, led to the establishment of narcotic clinics to legally provide heroin or morphine to individuals with addiction. By 1923, all these clinics had closed, deemed failures because they did not lead to abstinence. Federal agencies interpreted the 1914 Harrison Act as prohibiting maintenance of individuals with active addiction and threatened or prosecuted physicians doing so. Between 1919 and 1935, approximately 25,000 physicians were indicted under the Harrison Act and 10% were imprisoned. Despite 1921 and 1926 Supreme Court rulings that the act did not forbid such prescribing, most physicians avoided it, ending the role of the medical profession in treating patients with addiction for 4 decades.

Heroin became the street narcotic of choice. During World War II, with heroin scarce and purity as low as 1%, addiction hit a record low. By the late 1940s, the flow of smuggled heroin had resumed, but addicts were more likely younger, from a racial or ethnic minority group, and living in northern impoverished communities. Treatment was scarce, prison common, and relapse likely.³

Methadone Maintenance

Forty years after the last maintenance clinics closed, the 1965 article by Dole and Nyswander landed with a bang.¹ Dole, an internist, believed narcotic addiction was a metabolic disease, not very different from diabetes; Nyswander, a psychiatrist, had frustrating years of treating individuals with narcotic addiction with psychotherapy only to see them relapse. Their study,¹ conducted in New York City first at the Rockefeller Institute and later moving to Manhattan General Hospital, included 22 participants with heroin addiction. One year later, Dole et al reported empirical data on the induced narcotic blockade.⁴  Long-term follow-up studies later confirmed that therapeutic success on a larger scale was possible.

Methadone replaced morphine as the preferred agent for heroin withdrawal. As a maintenance agent for treating addiction, methadone prevents withdrawal for 24 to 36 hours, enabling a system in which addicted patients come for treatment once a day, in contrast to the 1920s clinics using short-acting opioids.

Following the 1965 article,¹ scientists systematically expanded the science behind methadone maintenance treatment (MMT). Large-scale programs using more cost-effective induction methods opened in New York City, and the US Food and Drug Administration approved a limited use of methadone in large research programs.⁵

In 1970, the federal government faced 2 major heroin-related problems: heroin use and associated crime was increasing, especially in urban areas; and soldiers in Vietnam were using heroin. Concerned about possible increased crime when these soldiers returned home and influenced by the early success of DuPont's Narcotics Treatment Administration in reducing crime by treating individuals with heroin addiction,⁶ President Nixon announced the war on drugs on June 17, 1971, created the Special Action Office for Drug Abuse Prevention (SAODAP), and hired Jerome Jaffe to be its first director. This new federal structure was charged with coordinating and rapidly expanding drug treatment, including changing existing regulations.⁵

Even as SAODAP and New York City moved to expand MMT, strong reaction began against it, fueled partly by reports of methadone-related deaths and diversion, but primarily by its substituting one addiction for another. Psychosocial program advocates opposed MMT as likely to reduce concerns about poverty and social ills. The director of a therapeutic community remarked, "I think methadone is a great idea. We should give money to bank robbers, women to rapists, and methadone to addicts."⁷

In those first 2 years, more federally supported treatment capacity developed than in the previous 50 years. In 1974, two-thirds of the $750 million drug budget was devoted to treatment, research, and prevention, compared with the recent 25 years during which two-thirds of the budget targeted supply reduction.⁵

Positive Outcomes of MMT

Numerous studies have demonstrated the effectiveness of MMT for reducing illicit opioid use, morbidity and mortality, risk of human immunodeficiency virus (HIV) infection, illegal activities, and improving overall functioning. Patients in MMT had a 1-year mortality rate of 1% compared with 8% among patients who discontinued treatment.⁸ In a 1993 prospective study conducted in Philadelphia, Pennsylvania, HIV seroconversion rates were 4 times higher among individuals who were actively using street heroin compared with patients receiving MMT.⁹ Risk decreased in relation to length of time continuously receiving MMT; risk of hepatitis B and hepatitis C also was reduced but to a much lower extent.⁹

In a 1991 study, crime days per year among individuals addicted to narcotics decreased more than 70% while receiving MMT.¹⁰ In a random assignment study, patients in the standard and enhanced treatment groups had marked reductions in illicit opiate use and improvements in overall functioning compared with the minimal counseling group.¹¹ However, the increase of for-profit MMT centers (often realizing very large profits), and decreased funding for nonprofit centers left many programs inadequately staffed. This remains a major unresolved public health problem.

Average methadone maintenance doses of 60 to 120 mg or higher have consistently better results than use of lower average doses, especially because heroin purity is now often greater than 40%. Methadone's plasma half-life, once stabilized, averages 24 to 36 hours with a range of 13 to 56 hours. However, as many as 10 days may be needed to reach a steady state, and new patients, either to MMT or given methadone for analgesia, are at risk for fatal overdose. Most deaths have been from methadone prescribed for pain rather than from methadone treatment programs.

Although MMT has been lifesaving for thousands of individuals, it is not a panacea. High levels of psychopathology remain. Abuse of cocaine and benzodiazepines and disruptive behavior are problems in many programs. Many patients do not change their behavior even when services are available. What to do under such circumstances remains contentious, given the likely severe postdischarge consequences vs the effect on other patients and the possibility that more intensive residential intervention might be helpful.

During the past 2 decades, evidence has accumulated regarding the neurobiology of opiate dependence. Opiate dependence is now seen as a brain-related disorder with genetic and environmental overlays characteristic of a medical illness. The endorphin system and opioid receptors have now been discovered. Dole was ahead of his time.^{1, 4, 12}

Safety

Studies on MMT in the 1970s by Kreek found no long-term damage to the heart, kidneys, liver, or lungs.¹³ Long-acting maintenance medications normalized the neuroendocrine alterations induced by short-acting opioids¹² with minimal psychoactive impairment. MMT has been shown not to impair driving ability. In the past decade, it was found that methadone, especially at high doses, when beginning treatment, or when combined with certain drugs, may lead to QTc prolongation and possibly to torsade de pointes, a potentially fatal cardiac arrhythmia. A black box warning was added to the prescribing information for methadone in December 2006. However, the clinical significance of this abnormality is not yet clear regarding deaths.

Federal Regulations

MMT is one of the most heavily regulated medical treatments in the United States.⁵ With few exceptions, methadone may only be dispensed for opioid withdrawal or maintenance by certified opioid treatment programs. An increasing number of take-home doses is permitted, depending on the patient's history of illicit drug use and employment, with a maximum 1-month supply after 2 years. Regulations and decreased public financing have made it more difficult to start or expand programs. An Institute of Medicine review¹⁴ concluded, " . . . current policy puts too much emphasis on protecting society from methadone, and not enough on protecting society from the epidemic of addiction, violence, and infections that methadone can help reduce." However, regulation that is too lenient may lead to worsened problems and increased hostility; a balance is needed.

Stigma

In the late 1980s, the backlash against MMT became stronger. Community complaints about loitering and bartering of drugs outside clinics exacerbated the hostile environment. Complaints often coincided with decreased ancillary supports.

In 1988, the White House Conference for a Drug-Free America, vehemently antimethadone, demonized methadone and the National Institute on Drug Abuse and called for a congressional investigation.⁷ In 1990, the Office of National Drug Control Policy reversed this position, and its White Paper on treatment stated clearly that methadone maintenance was both legitimate and an important part of the spectrum of drug abuse treatment.⁷ Ironically, even though 12-step programs have often been hostile to MMT,¹⁵ Dole, a friend of the cofounder of Alcoholics Anonymous recounted, "He [Bill W.] suggested that in my future research, I should look for an analogue of methadone, a medication that would relieve the alcoholic's sometimes irrestible craving and enable him to progress in AA toward social and emotional recovery. . . . "¹⁵

In the United States, approximately 260 000 individuals are currently receiving MMT (M. Perrino, written communication, October 2008), although it is estimated that fewer than 10% of individuals who are addicted to heroin and prescription opioids are receiving MMT. Worldwide, about 1 million individuals are receiving MMT; in some countries such as Russia, government opposition to agonist maintenance prevents its use even when high HIV rates exist.

The long-acting sublingual partial agonist buprenorphine, a Schedule III opioid, has been available since 2002 for office-based prescribing by physicians with special training⁵ and with current limits of 100 patients per physician. Approximately 140 000 patients are now receiving maintenance using buprenorphine (R.E. Johnson, written communication, October 2008) and results to date appear comparable to MMT albeit with somewhat different populations. It is not clear whether it will be any easier to remain abstinent after withdrawal from buprenorphine treatment than from MMT, especially if inadequate ancillary support is provided. While buprenorphine's formulation makes overdose or diversion to parenteral use less likely, like all µ agonists, this drug has that possibility and limited diversion is already occurring.

Methadone: Terminable or Interminable

The benefits of long-term methadone maintenance are borne out by data.² Two years of MMT appears to be the minimum duration before attempting withdrawal.⁵ Even patients receiving maintenance for long periods with substantial lifestyle changes often relapse after leaving treatment, and death rates are much higher than for individuals who remain in treatment. For many patients, therefore, years or even lifetime maintenance may be needed, but there is often patient and family opposition. Office-based medical maintenance has been used on a limited basis for patients stable at least a few years with generally successful results, although some patients increased their use of illicit drugs. This approach avoids the clinic problem of mixing stable and unstable patients but the number of eligible stable patients appears limited. Ultimately, the problem of interminable maintenance vs relapse may require learning how to reverse the brain changes associated with addiction. Until then, long-term agonist treatment remains a reasonable alternative.

AUTHOR INFORMATION

Corresponding Author: Herbert D. Kleber, MD, Columbia University College of Physicians and Surgeons, Division on Substance Abuse, The New York State Psychiatric Institute, 1051 Riverside, PI ^{Unit 66, New York, NY 10032 (hdk3@columbia.edu).}

Financial Disclosure: Dr Kleber reports serving as a consultant and also receiving an unrestricted educational grant from Reckitt Benckiser for the Columbia Buprenorphine Program through Columbia University.

Funding/Support: Support for preparation of this article was provided under: National Institute on Drug Abuse grant 5KO5 DA014284.

Additional Contributions: Progress in this area would not have been possible without the efforts and accomplishments of the many individuals who played important roles over the 40 years in expanding the science and growth of methadone maintenance. Their contributions made this potentially life-saving modality available to many.

Author Affiliations: Columbia University College of Physicians and Surgeons, Division on Substance Abuse, The New York State Psychiatric Institute, New York.

REFERENCES

1.Dole VP, Nyswander MA. Medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA. 1965;193(8):646-650. (PDF Format)

2. National Institutes of Health. Effective medical treatment of opiate addiction. NIH Consensus Statement. 1997;15(6):1-38. (PDF Format)

3. Jonnes J. Hep-Cats, Narcs, and Pipe Dreams. New York, NY: Scribner; 1996.

4. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med. 1966;118(4):304-309. (PDF Format)

5. Jaffe JH, O’Keeffe C. From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States. Drug Alcohol Depend. 2003;70(2 suppl):S3-S11.

6. DuPont RL. Heroin addiction in the nation's capital, 1966-1973. In: Musto DF, ed. One Hundred Years of Heroin. Westport, CT: Auburn House; 2002:67-90.

7. Kleber HD. Methadone: the drug, the treatment, the controversy. In: Musto DF, ed. One Hundred Years of Heroin. Westport, CT: Auburn House; 2002:149-158.

8. Zanis DA, Woody GE. One year mortality rates following methadone treatment discharge. Drug Alcohol Depend. 1998;52(3):257-260.

9. Metzger DS, Woody GE, McLellan AT; et al. Human immunodeficiency virus seroconversion among intravenous drug users in and out of treatment: an 18 month prospective follow-up. J Acquir Immune Defic Syndr. 1993;6(9):1049-1056.

10. Ball JC, Ross A. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer Verlag; 1991.

11. McLellan AT, Arndt IO, Metzger DS; et al. The effects of psychosocial services in substance abuse treatment. JAMA. 1993;269(15):1953-1960.

12. Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA. 1988;260(20):3025-3029. (PDF Format)

13. Kreek MJ. Medical complications in methadone patients. Ann N Y Acad Sci. 1978;311:110-134.

14. Rettig RA, ed, Yarmolinsky A, ed. Federal Regulation of Methadone Treatment. Washington, DC: Institute of Medicine National Academy Press; 1995.

15. Dole VP. Addiction as a public health problem. Alcohol Clin Exp Res. 1991;15(5):749-752.

Download: Methadone Maintenance 4 Decades Later. (PDF Format)

Variations In Key Genes Increase Caucasians’ Risk Of Heroin Addiction

ScienceDaily (Oct. 5, 2008)

Sometimes, small changes do add up. In the case of addictive diseases, tiny variations in a few genes can increase or decrease the likelihood of some people developing a dependency on heroin. Now, by examining a select group of genetic variants in more than 400 former severe heroin addicts, Rockefeller University researchers have identified several genetic variations in American and Israeli Caucasians that influence the risk for becoming addicted to one of the world’s most powerful substances.

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In a collaborative effort with statistical geneticists and several methadone clinics, scientists led by Mary Jeanne Kreek, head of the Laboratory of the Biology of Addictive Diseases, analyzed 1,350 variations in 130 genes and found nine, from six genes, that were either more or less common in recovering heroin addicts when compared to Caucasians with no history of drug abuse. These small changes in the gene sequences can cause significant changes in protein function that can influence addictive behavior — changes that may affect people of different ethnic background differently.

“The idea of ‘personalized medicine’ makes this field really exciting but also very complicated,” says Orna Levran, a senior research associate in the Kreek laboratory and first author of the study. “Although seven of these variants increase the risk for developing heroin addiction in Caucasians, the same seven may not have the same effect in other populations. So ethnicity and, more precisely, genetic information in each individual may become important factors for treating and diagnosing addictions to different drugs.”

In their analysis, Kreek, Levran and their colleagues looked at a string of letters called nucleotides, the building blocks that make up genes. In each of the six genes, at least one letter is replaced by another, a genetic variation known as a single nucleotide polymorphism, or SNP. The researchers found that all of the single-letter variations exist in parts of the genes that do not translate into proteins but instead may have a regulatory or a structural effect.

Out of the nine SNPs, the group found six in the μ, δ and κ opioid receptors, a finding that reinforces the idea, and many other findings of the Kreek laboratory, that opiate receptors play a major role in severe heroin addiction. The remaining three SNPs were found in genes coding for the serotonin receptor 3B, casein kinase 1 epsilon, which acts as a regulator of the circadian clock genes, and galanin, which modulates appetite and alcohol consumption. This is the first study to show that specific variants in these genes are associated with heroin addiction, explains Levran.

The SNPs in the κ opioid receptor and casein kinase 1 genes were found more in the control group than the heroin addicts’ group, suggesting that they conferred protection from heroin addiction — not vulnerability to develop addiction.

“Individually, these SNPs probably have a small effect,” explains Levran, “but collectively, we are seeing that they could have a larger effect. One of the goals now is to find all of these gene variants and assess how they influence people of different ethnic backgound.”

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Journal reference:

Levran, Londono, O'Hara, Nielsen, Peles, Rotrosen, Casadonte, Linzy, Randesi, Ott, Adelson, Kreek. Genetic susceptibility to heroin addiction: a candidate gene association study. Genes Brain

and Behavior, 2008; 7 (7): 720

Adapted from materials provided by Rockefeller University.

ABSTRACT

Genetic susceptibility to heroin addiction: a candidate gene association study

O. Levran*,†, D. Londono ‡ , K. O'Hara † , D. A. Nielsen † , E. Peles § , J. Rotrosen ¶ , P. Casadonte ¶ , S. Linzy**, M. Randesi † , J. Ott ‡,†† , M. Adelson †,§,** M. J. Kreek †
  † The Laboratory of the Biology of Addictive Diseases, and  ‡The Laboratory of Statistical Genetics, The Rockefeller University, New York, NY, USA,  §Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Tel Aviv Elias Sourasky Medical Center, Tel Aviv, Israel,  ¶VA New York Harbor Healthcare System and NYU School of Medicine New York, NY and  **Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse, Treatment and Research, Las Vegas, NV, USA, and  ††Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

Correspondence to   *O. Levran, The Laboratory of the Biology of Addictive Diseases, 1230 York Avenue, Box 171, The Rockefeller University, New York, NY 10065, USA. E-mail: levrano@rockefeller.edu

Copyright Journal compilation © 2008 Blackwell Publishing Ltd/International Behavioural and Neural Genetic Society

KEYWORDS: Association study, candidate gene, heroin addiction

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in noncoding regions of the genes encoding the mu (OPRM1; rs510769 and rs3778151), kappa (OPRK1; rs6473797) and delta (OPRD1; rs2236861, rs2236857 and rs3766951) opioid receptors; the neuropeptide galanin (GAL; rs694066); the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multilocus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction, which is worthy of future study.

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Byrne Review: Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.

Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J.  Journal of Addictive Diseases 2008 27;3:31-35

These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a ‘normal’ addiction clinic setting. 

We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls.  Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world.  Most subjects were in their 30s and 28 of 71 (39%) were female. 

No significant difference in QT interval was found between the three groups.  There were 2 methadone patients and one control with long QT when defined as 430ms or longer for males (450 for females).  None was over 475ms (the threshold at which risk of torsades occurs is believed to be 500ms).  There was a trend for longer QT intervals in those on >60mg daily as well as some increased U waves reported in methadone patients.  These findings are consistent with Lipsky’s findings from 1973, but the clinical significance, if any, is unclear.  Like other prospective studies on this subject, these authors do not report any cases of torsades. 

The authors conclude: “Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.” 

As an exercise I contacted two prominent addiction experts in Adelaide on this subject.  One had seen no cases and the other was aware of one possible case some years ago.  This is on a long background of good quality methadone treatment, both private and public, in that city. 

It may be timely to examine the evidence for claims that methadone treatment in addiction is accompanied by a significant risk from arrhythmias, including death.  Despite there being no body of case reports (or perhaps because of it) a number of authors attempted to assess methadone’s role in cardiotoxicity by using indirect and unconventional methods. 

For example, Fanoe (ref below) prefers QT/torsades as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen.  Since the incidence of torsades is 0-1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics).  Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood.  His deduction for QT changes without a single case report seems hard to understand.  Wedam (ref below) wrote “To compare the effects of …[methadone] … on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.”  [our italics]   In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms.  This is not consistent with other reports on the subject.  No torsades cases were reported in the study groups. 

A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors.  Few of these reported cases bear much similarity to those commencing ‘normal’ clinic or community addiction treatment.  The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold ‘normal’ doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome). 

I believe that it is now possible to restate unequivocally that ‘normal’, guideline-based methadone treatment is safe and effective.  The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment.  Knowing the risk factors, most cases could probably be avoided using good clinical practice (see Sticherling).  A pre-treatment cardiograph would not have detected any of these cases. 

As well as a dearth of relevant case reports, some have given advice without due consideration of the benefits of methadone treatment in the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko).  While methadone induced torsades may indeed occur, it must be in extremely low numbers and would probably be swamped statistically by reductions in endocarditis cases alone (as reported by Krantz in 2001 - ref below). 

In practical terms, this means that existing methadone patients needing other medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should have a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course. 

We need to ensure that as clinicians we continue to ask the question: what is the evidence? 

Comments by Andrew Byrne ..

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References:

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282–285

Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml

Byrne Review: QTc Interval Prolongation and Opioid Addiction Therapy.

Baker WA, Krantz MJ. Archives Internal Medicine (letter) 2008 168;14:1502

In this letter Baker and Krantz applaud Wedam et al’s ‘commendable’ “addition to the medical literature” which found QT prolongation in 23% of methadone subjects.  In fact these researchers found much the same as Janet Lipski’s report from 1973 (34%).  Thus it is clear that a substantial minority of methadone patients have modest prolongation of QT intervals of uncertain significance. 

Baker and Krantz then express the unsurprising deduction that if a lower cut-off for QT prolongation were used, a correspondingly higher proportion of prolongation subjects will result (up to 50%).  The clinical significance of these observations, if any, is not detailed.  Indeed, not a single subject in the entire study had a QT interval (corrected) of 500ms or more which is considered by some authorities to be the clinically significant cut-off for risk of tachycardia.  And none developed tachycardia. 

Krantz has wrongly cited Lipski’s study as being (at least in part) to investigate sudden deaths in methadone patients.  In fact, Lipski and colleagues were concerned about heroin deaths and the QT findings in methadone patients were incidental.  When this mistake was pointed out in Lancet, Krantz in reply ignored the matter and turned to increasing deaths of non-addiction treatment (pain) cases in America more recently (Mehler 2007). 

Specifically, Krantz writes that Lipski’s study was aimed at investigating “a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone” in 1973 in New York (Krantz MJ 2006).  From the title and opening lines it is clear that Lipski and colleagues were actually concerned over deaths in heroin users where sometimes blood levels were not particularly high, an issue raised by long time city coroner Dr Milton Helpern (see ref).  They performed cardiographs in new methadone applicants who had used street heroin in the previous hours or day(s) to see if there were any electrical disturbances which might explain the sudden deaths in heroin users. 

Unlike in his first paper on this subject, Krantz now treats QT prolongation in isolation as if it were a complication in itself, avoiding discussion of torsades or other cardiac events.  And like most of the other studies, Wedam and colleagues report no symptomatic heart disease whatever and, most importantly, no sudden deaths.  Over a period of 30 years of intensive, supervised prescription of methadone only one single case of arrhythmia was reported to the FDA (Pearson).  So while torsades or ventricular fibrillation occur in methadone patients, the prevalence must be very low and possibly near to the rate in the general population (estimated to be 1 in 2000 - see Smith W).

This laudatory letter is just another ‘weak link’ in the case put by Krantz that due to potential cardiac complications, methadone treatment needs to be reviewed, especially when used in high doses.  He recently noted ‘with consternation’ (hardly a scientific term) that higher doses were being used in addiction clinics in his own state, something most public health specialists would have applauded (D’Aunno).  Many rigorous studies indicate that higher doses protect dependency patients from significant and measurable events (overdose, viral disease, criminal behaviour, depression, etc).  Dole’s seminal study of methadone treatment reported up to 180mg daily with excellent results and no serious side effects. 

To my knowledge there have still been no reported series of confirmed case reports of cardiac complications (eg. torsades-de-pointes) in patients receiving methadone treatment for addiction under existing guidelines.  Krantz emphasises the proven benefits of MMT yet at the same time questions this established, evidence-based practice, emphasising a difficult therapeutic “trade-off”.  Yet this is before there is documented evidence of a problem existing and despite 30 years of careful research showing safety and effectiveness.  Further, there has been no analysis of the costs and benefits of any suggested alternative strategies such as low dose methadone or transfer to buprenorphine.  Krantz has also apparently had minimal input from dependency specialists.  Few non-cardiologists would be so bold regarding advice on heart treatments. 

Dr Krantz's widely publicized views have had the consequence of denigrating methadone as a treatment for both addiction and chronic pain.  I can find no evidence suggesting that  any cases of cardiac complications resulting from methadone treatment have been avoided as a result.  The literature reveals only flimsy and conflicting evidence - most of it retrospective - of an association of methadone and cardiac events.  Some have reported a lower cardiac risk (Marmor 2004). 

Krantz's articles, letters and personal communications show a clear 'disconnect' between his earlier findings and the sentiments he has expressed more recently.  While his earlier findings relate mostly to pain patients, he has strongly targeted an addiction treatment audience for his communications and further research (eg. Krantz 2007).  His advice, which has changed over the years, has involved (1) the need (or otherwise) for a cardiograph before starting treatment, (2) the avoidance of methadone where possible and (3) the avoidance of high doses where methadone is used.  His other recommendations are purely generic in recommending careful history and physical on each patient and acting on any evidence of cardiac risk.  While this is important, it is probably no more important than acting on evidence of infectious disease, overdose risk, liver disease, allergies, mental illness, etc, etc.

The potential risk of cardiac side effects must be balanced against the unequivocal benefits of methadone maintenance to those who need and want it for their condition.  There need be no ‘competition’ with buprenorphine which is an excellent alternative with certain benefit and certain disadvantages in the opiate treatment population. 

Comments by Andrew Byrne ..

References:

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

Mehler PS, Krantz MJ. Authors’ reply. Methadone and QTc prolongation. Lancet 2007 369:366-7

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50  '193(8) 80-84'

Helpern M. Fatalities from narcotic addiction in New York City: incidence, circumstances and pathologic findings. Human Pathology 1972 2:13-21

Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004;93:1295-1297

Leavitt S. Methadone: facts and fiction. Available from: ATForum.com.

Byrne Review: A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release.

Gordon MS, Kinlock TW, Schwartz RP, O'Grady KE. Addiction 2008 103;8:1333-1342

These researchers found, predictably, that offering methadone maintenance treatment (MMT) to released prisoners with a history of opiate addiction was feasible, safe and effective, just like it is in the community generally when done according to established guidelines.  They compared counselling with/without MMT, finding less heroin use and less criminal activity at 6 months after release in those offered MMT.  Treatment retention was also higher. 

This is yet another example of American clinical practice which is decades behind other countries.  And this is despite heroin addiction has been accepted as a ‘brain disease’ by the White House and methadone/agonist treatments are now approved in every state.  However, for those in the US prison system these maxims do not apply for some reason.  Note that this study was not published in an American journal. 

Almost uniquely, in New South Wales, prisoners have had access to methadone treatment for over 20 years.  It was initially introduced in the 1980s as a pre-release measure to address the high rate of overdoses in that group.  There is now a copious world literature on the subject, largely very positive.  Methadone for prisoners has now been introduced in many other jurisdictions, although rarely ‘across the board’ as occurs in New South Wales. 

Thus a trial which gave some subjects no access to such treatment would be unethical, unnecessary and cruel in a ‘normal’ jurisdiction.  Yet in America, despite a large drug budget and constitutional protections, denying prisoners appropriate treatment seems to be ‘business as usual’.  These researchers should be commended for trying to buck the trend.  They write that there is an “urgent treatment need” and one only hopes that something is done for the sake of the prisoners, their families and the general community where the adverse consequences currently must be enormous. 

Comments by Andrew Byrne ..

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