Benzodiazepine maintenance from clinic setting.

Of Substance 2010 Vol 3 p11 ‘Research digest’.

View from the coalface … Redfern, inner Sydney
Andrew Byrne*


After many years of wrestling with the problem of
benzodiazepine use in opioid-dependent patients, it was
reassuring to read this prominent paper by Liebrenz
and colleagues. Their hypothesis is an approach using
what appear to be harm reduction principles, parallel to
methadone maintenance. Our original practice policy
was to ‘just say no’ but despite our entreaties, about one-
third of our patients continued to use benzodiazepines on
urine testing. A number did succeed at abstinence, only to
relapse with significant harms occurring due to disinhibited
behaviour, often involving amnesia of the events.

Some patients were able to function almost normally
while taking illicit benzodiazepines. Others became
disorganised regarding their finances, housing and
interpersonal relationships, some even coming to the
attention of the police or emergency departments.

Although there appeared to be a number of patterns
of tranquilliser use, from binge and recreational use to
quasi-therapeutic, we treated all such patients the same
way initially, using diazepam 5mg tablets supervised at the
clinic. Those currently abusing alcohol were excluded.
Each patient needed to return at least once, about three
hours after a witnessed dose for a brief examination to
confirm their tolerance and exclude intoxication. All
patients also had to agree to random urine testing and
regular medical consultations to assess progress.

Our impression has been that when given access to
diazepam under close supervision, stability returned
to most such patients. A recent audit of our referral
dependency practice showed that of 167 pharmacotherapy
patients (80% methadone, 20% buprenorphine), 30%
were being prescribed benzodiazepines, mostly under
supervision. The mean dose was 14 mg daily (range
2mg-25mg). One-third were gainfully employed.

Thus we can confirm that some of the protocols alluded
to in the forward-thinking item in Addiction are feasible
and are ripe for research. Inquiries showed that many of
our colleagues had one or two pharmacotherapy patients
taking long-term benzodiazepines and nearly all had
organised supervised dosing at least once.

Benzodiazepine use has been the ‘elephant in the room’
in addiction treatment. While most centres still use an
abstinence approach, many patients continue to use
these drugs. Since benzodiazepines, along with alcohol,
constitute a major source of drug-related harm, it may
be timely to reassess our approach. Severe restrictions
on supply alone have historically never solved drug
problems. Such restrictions also necessarily reduce access
to those who need the drugs therapeutically. As with
many other areas of public health, we believe that it is
possible to translate the principles of ‘harm reduction’ to
benzodiazepine use by utilising the protocols of ‘universal
precautions’ espoused by Dr Gourlay in Canada.

The use of benzodiazepine maintenance is probably at
the same stage of ‘evidence’ as methadone treatment was
in about 1980. It appears to be acceptable to the patient
population; it appears to be safe in practice, yet definitive
research is awaited to prove its effects … and to identify
optimal dosing, supports and necessary supervision.

* Dr Andrew Byrne is a Sydney GP specialising in
drug dependency.

http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf [full newsletter download]


Byrne A. View from the coalface … Redfern, inner Sydney. Of Substance. 2010;3:11

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction. 2010 Apr 27 Early View

Stringer response, page view: full text below. Does electrocardiography improve methadone safety?

Does electrocardiography improve methadone safety? Byrne A, Hallinan R, Newman RG. Am J Health Syst Pharm 2010 67:968-969


Dear Editor,

We commend Stringer and colleagues’ excellent summary of the literature on this subject. However we would question the recommendation to perform electrocardiography (ECG) prior to and during the course of methadone treatment as a measure to prevent torsade de pointes (TdP) tachycardia [1]. Even close reading does not reveal a justification for such advice. The authors need to make a case that TdP is a problem in clinical practice and then demonstrate how ECG would or could prevent the occurrence of this serious event. We believe that neither of these requirements has been satisfied. Even if they were, the proposed intervention should still be tested in the field for efficacy. There is still no accepted incidence for torsade de pointes and we were unable to find any confirmed deaths resulting directly from this complication among the 105 cases reported in the literature. ‘Indirect’ or suspected deaths still only number in single figures to our best knowledge.

Stringer et al. cite 37 cases of TdP from 19 authors (refs 22 to 40). An analysis of these shows that of the 16 for whom a QTc measurement is quoted away from the torsade episode, only 4 were prolonged (>460ms). In addition, there was a clear precipitant in nearly all cases, commonly alcohol/cocaine use, hypokalemia or prescribed medication. Thus ECG could only have identified a small proportion of such reported cases (0-18%). Furthermore, any proposed clinical strategy of avoiding methadone or using lower doses would have negative consequences regarding retention and increased mortality, largely from overdose. This is based on a good quality studies showing somewhat better retention rates with methadone than buprenorphine as well as better retention rates with the use of high doses versus low doses of methadone.

Although surely used for decades by many addiction programs as well as in other clinical settings, the strategy of routine ECG has not been shown to reduce arrhythmia problems (if any) in methadone prescribed patients. Even where significant cardiac abnormalities are detected before or during treatment with methadone, the consequences of withholding this medication would have to be carefully balanced by the clinician. In this connection it is important to note that the likelihood of morbidity and mortality associated with untreated opioid dependence is vastly greater than what evidence suggests might be expected as a result of potential cardiac perturbations caused by methadone. Krantz has called the balancing of risks and benefits in this instance a clinical paradox [2] yet it is precisely what doctors do with all prescribing decisions, and indeed with consideration of any and all medical management options.

Stringer and colleagues quote Farnoe and Chugh [3,4] to justify the contention that there may be more torsade cases than currently reported, in non-fatal and fatal circumstances respectively. These studies use two indirect and questionable methodologies to conclude that TdP may be a frequent occurrence in methadone patients. Neither paper described any cases of tachycardia. Furthermore, of 22 deaths in Chugh’s paper seven (32%) used methadone from unknown or illicit sources.

More recently a large national study from Norway found fatal TdP to be rare to non-existent in methadone treatment for addiction [5]. Anchersen and colleagues reported secure causes of death in 86 out of 90 sudden deaths in a 7 year period in over 2000 patients prescribed methadone maintenance for addiction. None was reportedly as a result of arrhythmia nor did any of their volunteer sample of 200 report arrhythmia. Even if all 4 uncertain deaths were taken as possible TdP case, the low rate of 0.06 per 100 patient years would have been inconsistent with the conclusions of Farnoe and Chugh.

In conclusion we would suggest that patients should be treated individually with a detailed history and focused physical examination before starting on methadone treatment. In the current state of knowledge ECG is just as likely to cause problems as avert them in our view. If funds are available for clinic screening then needs-based toxicology, hepatitis, HIV and lipid tests would be higher priority for most injecting drug users.

Authors: Andrew Byrne*; Richard Hallinan*; Robert G. Newman#

* Byrne Surgery, 75 Redfern St, Redfern, NSW, Australia.
# The Baron Edmond de Rothschild Chemical Dependency Institute, BMIC, 555 W. 57th St., NY NY 10019

Conflict statement: Dr Byrne owns a clinic which charges a fee for dispensing of medications in the treatment of addictions.


References:

1. Stringer J, Welsh C, Tommasello A. Methadone-associated Q-T interval prolongation and torsades de pointes. Amer J Health-Syst Pharm 2009 May 1;66(9):825-833

2. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368;9535:556-557

3. 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

4. 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

5. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

Further comment on the Stringer paper: http://methadone-research.blogspot.com/2010/05/advice-to-stop-methadone-could-be.html

Naltrexone implant study problematic

http://archpsyc.ama-assn.org/cgi/eletters/66/10/1108#13504

Readers Reply to:

Original Article:
Gary K. Hulse; Noella Morris; Diane Arnold-Reed; Robert J. Tait.
Improving Clinical Outcomes in Treating Heroin Dependence: Randomized, Controlled Trial of Oral or Implant Naltrexone.
Arch Gen Psychiatry 2009; 66: 1108-1115 [Abstract] [Full text] [PDF]


Electronic letters published:

Naltrexone implant study problematic
Andrew Byrne (27 January 2010)

[see link above]

Other Recent Byrne Surgery Publications.

1. Med J Aust. 2009 Sep 21;191(6):302-3.

Improving the management of chronic non-malignant pain and reducing problems associated with prescription opioids.

Wodak AD, Cohen ML, Dobbin MD, Hallinan RA, Osborn M.

St. Vincent's Hospital, Sydney, NSW, Australia. awodak@stvincents.com.au

New guidelines and a multidisciplinary approach have the potential to help patients in need while minimising inappropriate use of opioids.

PMID: 19769550 [PubMed - indexed for MEDLINE]

http://www.mja.com.au/public/issues/191_06_210909/wod10633_fm.html


2. Eur J Clin Pharmacol. 2009 Nov;65(11):1113-20. Epub 2009 Jul 29.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

Hallinan R, Crettol S, Agho K, Attia J, Besson J, Croquette-Krokar M, Hämmig R, Déglon JJ, Byrne A, Ray J, Somogyi AA, Eap CB.

The Byrne Surgery, Redfern, NSW, Australia.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose.

RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4.

CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

PMID: 19639308 [PubMed - indexed for MEDLINE]


3. J Sex Med. 2008 Mar;5(3):684-92. Epub 2007 Dec 18.

Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.

Hallinan R, Byrne A, Agho K, McMahon C, Tynan P, Attia J.

The Byrne Surgery, Redfern, Sydney, NSW, Australia. reichall@iprimus.com.au

INTRODUCTION: Use of opiates/opioids is associated with hypoactive sexual desire, erectile and orgasmic dysfunction. AIM: To determine prevalence and investigate etiology of sexual dysfunction in men on methadone or buprenorphine maintenance
treatment (MMT, BMT).

MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF), hormone assays, Beck Depression Inventory. METHODS: A total of 103 men (mean age 37.6 +/- 7.9) on MMT (N = 84) or BMT (N = 19) were evaluated using the IIEF, hormone assays, Beck Depression Inventory, body mass index (BMI), demographic, and other substance use measures.

RESULTS: Mean total IIEF scores for partnered men were lower for MMT (50.4 +/- 18.2; N = 53) than reference groups (61.4 +/- 16.8; N = 415; P < 0.0001) or BMT (61.4 +/- 7.0; N = 14; P = 0.048). Among partnered men on MMT, 53% had erectile dysfunction (ED) compared with 24% of reference groups; 26% had moderate to severe ED, 12.1% in under 40s and 40.0% among those 40+ years. On multiple regression, depression, older age, and lower total testosterone were associated with lower IIEF and EF domain; on multivariate analysis, there were no significant associations between IIEF or EF and free testosterone, opioid dose, cannabis or other substance use, viral hepatitis, or BMI. Total testosterone accounted for 16% of IIEF and 15% of EF variance. Men without sexual partners had lower Desire and Erection Confidence scores and less recent sexual activity, suggesting potentially higher prevalence of sexual dysfunction in this group.

CONCLUSION: Men on MMT, but not BMT, have high prevalence of ED, related to hypogonadism and depression. Practitioners should screen for sexual dysfunction in men receiving opioid replacement treatment. Future studies of sexual dysfunction in opioid-treated men should examine the potential benefits of dose reduction, androgen replacement, treatment of depression, and choice of opioid.

PMID: 18093096 [PubMed - indexed for MEDLINE]


4. Int J Androl. 2009 Apr;32(2):131-9. Epub 2007 Oct 30.

Hypogonadism in men receiving methadone and buprenorphine maintenance treatment.

Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, Attia J.

The Byrne Surgery, Redfern, NSW, Australia. reichall@iprimus.com.au

The aim of this study was to determine the prevalence and investigate the aetiology of hypogonadism in men on methadone or buprenorphine maintenance treatment (MMT, BMT). 103 men (mean age 37.6 +/- 7.9) on MMT (n = 84) or BMT (n = 19) were evaluated using hormone assays, body mass index (BMI), serological, biochemical, demographic and substance use measures. Overall 54% of men (methadone 65%; buprenorphine 28%) had total testosterone (TT) <12.0 nm; 34% (methadone 39%; buprenorphine 11%) had TT <8.0 nm. Both methadone- and buprenorphine-treated men had lower free testosterone, luteinising hormone and estradiol than age-matched reference groups. Methadone-treated men had lower TT than buprenorphine-treated men and reference groups. Prolactin did not differ between methadone, buprenorphine groups, and reference groups. Primary testicular failure was an uncommon cause of hypogonadism. Yearly percentage fall in TT by age across the patient group was 2.3%, more than twice that expected normally. There were no associations between TT and opioid dose, cannabis, alcohol and tobacco consumption, or chronic hepatitis C viraemia. On multiple regression higher TT was associated with higher alanine aminotransferase and lower TT with higher BMI. Men on MMT have high prevalence of hypogonadotrophic hypogonadism. The extent of hormonal changes associated with buprenorphine needs to be explored further in larger studies. Men receiving long term opioid replacement treatment, especially methadone treatment, should be screened for hypogonadism. Wide interindividual differences in methadone metabolism and tolerance may in a cross-sectional study obscure a methadone dose relationship to testosterone in individuals. Future studies of hypogonadism in opioid-treated men should examine the potential benefits of dose reduction, choice of opioid medication, weight loss, and androgen replacement.

PMID: 17971165 [PubMed - indexed for MEDLINE]