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Reply to Chai et al

  1. Hannah L. F. Cooper1,
  2. Joanne E. Brady2,
  3. Daniel Ciccarone3,
  4. Barbara Tempalski2,
  5. Karla Gostnell2, and
  6. Samuel R. Friedman2
  1. 1Rollins School of Public Health at Emory University, Atlanta, Georgia
  2. 2National Development and Research Institutes, New York, New York
  3. 3School of Medicine, University of California, San Francisco
  1. Reprints or correspondence: Dr. Hannah Cooper, Behavioral Sciences and Health Education, Rollins School of Public Health, Emory University, 1518 Clifton Rd. NE, Rm. 568, Atlanta, GA 30322 (hannah.cooper{at}sph.emory.edu).

To the Editor—We read with great interest the article by Chai et al. [1] regarding an increase in the number of hospitalizations for infections (including infective endocarditis [IE]) among injection drug users at Singapore's National University Hospital, Singapore, and its possible links to injected Subutex (Reckitt Benckiser), a formulation of buprenorphine hydrochloride. Chai et al. [1] posit that buprenorphine diversion (specifically, the injection of crushed buprenorphine tablets) may have driven the increases in the number of hospitalizations for IE among injection drug users in the United States between 2000–2001 and 2002–2003 [1, 2]. Buprenorphine is a partial µ-opioid receptor agonist and a Κ-opioid receptor antagonist and is approved in many countries as an opiate substitution therapy [3]. At adequate doses, buprenorphine has proven to be an effective treatment for opiate dependence that reduces overdose morbidity and mortality and the incidence of HIV infection among opiate-dependent individuals [3, 4]. Consequently, in 2005, the World Health Organization added buprenorphine to its “Model List of Essential Medications” for substance-dependence treatment [5]. Governments approving access to buprenorphine for the treatment of opiate dependence are, thus, fulfilling the public's right to the highest attainable standard of health, as articulated in the International Covenant on Economic, Social, and Cultural Rights [6].

Determinants of single health outcomes can vary across geographic areas. Thus, although buprenorphine diversion may contribute to an increasing number of case of injection drug use–related IE in Singapore, there is no evidence to support the hypothesis that it does so in the United States. US surveillance systems have recorded few instances of buprenorphine diversion [3], perhaps because of federal policies governing buprenorphine prescribing. There are 2 sublingual formulations of buprenorphine available: Subutex and Suboxone (Reckitt Benckiser) [3]. Subutex contains only buprenorphine; Suboxone contains buprenorphine and naloxone hydrochloride [7]. Naloxone is an antagonist at the µ-opioid receptor, and Suboxone exploits naloxone's divergent sublingual and parenteral potency profiles [4, 7]. Naloxone's bioavailability is low (8%–10%) when administered sublingually [4, 7]; when injected, however, naloxone's bioavailability is substantially higher, and it induces withdrawal symptoms among individuals dependent on full opioid agonists [4, 7]. For this reason, the US Food and Drug Administration recommends that physicians prescribe Suboxone (not Subutex) after the initial period of buprenorphine therapy [8]. This recommendation was made to reduce the likelihood of injection of buprenorphine among individuals dependent on full opioid agonists [4, 8], and surveillance data suggest that this recommendation largely achieved its purpose [3].

Although non–opiate-dependent individuals may inject Suboxone, US surveillance data suggest that this practice is not widespread (C. Schuster, personal communication) [3], perhaps because naloxone attenuates buprenorphine's opiate agonist effects even among nondependent individuals [7]. Both the rigorous certification process that US physicians undergo to prescribe buprenorphine [4] and the cap on the number of cases each clinic can treat [4] may further reduce the likelihood of inadvertent prescribing to non–opiate-dependent individuals.

Moreover, the Food and Drug Administration approved Subutex and Suboxone as opioid-dependence therapies in late 2002 [8]. Because of slow uptake in 2003 [9], it is unlikely that either contributed substantially to the increase in the number of IE-associated hospitalizations in the United States between 2000–2001 and 2002–2003.

We, therefore, doubt that buprenorphine contributed to the increase in the number of IE-associated hospitalizations of injection drug users in the United States. Ensuring the continued availability of buprenorphine in the United States, while monitoring its possible adverse consequences, is a key step in an ongoing effort to ensure that federal, state, and local governments respect, protect, and fulfill drug users' right to health.

 
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Acknowledgments

Potential conflicts of interest. All authors: no conflicts.

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References

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    1. Chai LYA,
    2. Khare C,
    3. Chua A,
    4. Fisher DA,
    5. Tambyah PA
    . Buprenorphine diversion: a possible reason for increased incidence of infective endocarditis among injection drug users?. The Singapore experience. Clin Infect Dis 2008;46:953-5. (in this issue).
    FREE Full Text
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    1. Cooper HL,
    2. Brady JE,
    3. Ciccarone D,
    4. Tempalski B,
    5. Gostnell K,
    6. Friedman SR
    . Nationwide increase in the number of hospitalizations for illicit injection drug use-related infective endocarditis. Clin Infect Dis 2007;45:1200-3.
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    . Buprenorphine use: the international experience. Clin Infect Dis 2006;43(Suppl 4):197-215.
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    Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration. 2004.
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    World Health Organization (WHO). WHO essential medicines library. Available at: http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Accessed 10 December 2007.
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    Center for the Study of Human Rights at Columbia University. Twenty-five human rights documents. New York: Columbia University. 1994.
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    1. Mendelson J,
    2. Jones RT
    . Clinical and pharmacological evaluation of buprenorphine and naloxone combination: why the 4:1 ratio for treatment. Drug Alcohol Depend 2003;70(Suppl 1):29-37.
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    US Food and Drug Administration. Subutex and Suboxone approved to treat opiate dependence. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01165.html. Accessed 10 December 2007.
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    1. Koch AL,
    2. Arfken CL,
    3. Schuster CR
    . Characteristics of US substance abuse treatment facilities adopting buprenorphine in its initial stage of availability. Drug Alcohol Depend 2006;83:274-8.
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  1. Clin Infect Dis. (2008) 46 (6): 955-956. doi: 10.1086/528870
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