Thursday, November 20, 2008


Authors and Supporters:

Dr. M. Kahan, Dr. K. Arnold, Dr. R. Baker, Dr. K. Bertram, Dr. B. Conway, Dr. G. Cunningham, Dr. D. Coleman, Dr. S. deVlaming, Dr. F. Duncan, Dr. M. Durnin-Goodman, Dr. F. Evans, Dr. P. Farnan, Dr. P. Faye, Dr. K. Hossack, Dr. D. Hedges, Dr. K. Jiwa, Dr. A. Krishnamurthy, Dr. M. Khara, Dr. S. Lu, Dr. R. Mangat, Dr. A. Mead, Dr. J. Melamed, Dr. Reyes-Smith, Dr. C. Rucker, Dr. B. Russell, Dr. M. Viljoen,


As physicians who treat addiction, we have several concerns about the design and interpretation of the NAOMI trial.
·1 The objective of NAOMI was to find an effective alternative treatment for heroin addicts who have failed at methadone treatment. Yet many if not most of the subjects were early non-responders to methadone treatment, rather than treatment failures. Evidence suggests that such patients will respond to comprehensive treatment with optimal methadone dosing.
·2 The methadone arm received sub-optimal doses of methadone, while the total opioid dose in the heroin-methadone arm was substantially higher than that of the methadone group. Since the effectiveness of opioids in reducing heroin use is dose-related, this biases the results in favour of the heroin group.
·3 There were a significant number of serious adverse events in the heroin group, and its safety relative to methadone has not been established.
·4 Outcome measures were primarily subjective, and patients had been defined as ‘retained in treatment’ if they had dropped out of the trial but were in a detoxification facility. Detoxification facilities have high relapse rates unless they are linked with residential rehabilitation or opioid agonist treatment.
Pre-clinical studies are needed to demonstrate the safety of the iv heroin-methadone combination; we believe that this highly potent formulation should receive the same rigorous testing as other new medical treatments. Clinicians and policy makers need to agree on a clinically useful definition of treatment resistance, and to estimate the number of patients who meet this definition. Further outcome analyses are needed, for example, what were the on-treatment retention rates; what were the heroin reduction and abstinence rates for patients attending detox facilities or residential programs. Given the limitations of the NAOMI study, the establishment of hydromorphone injection clinics in BC is premature. Such a clinic will be expensive and of unproven efficacy and safety, and it may result in hydromorphone diversion and iv abuse in the community.
There are a number of cost-effective and practical strategies that will address the heroin crisis in the Downtown Eastside. We recommend the urgent establishment of comprehensive methadone and buprenorphine treatment clinics, with 600- 1000 treatment spots. The clinics should be staffed by physicians experienced at methadone dose titration. Counselling, outreach and case management should be available. Primary medical care should be provided on site, as well as specialized treatment for HIV and Hepatitis C. The clinic should have strong connections with detox centers, In Site and other facilities, so that heroin users can have immediate access to methadone treatment. Community methadone providers should receive additional training, appropriate compensation for counseling, and support from addiction counselors and case managers. Pharmacists also need extra training and support.

NAOMI: A Critical Appraisal

We are a group of addiction medicine physicians who have spent many years working with heroin users in Vancouver and Toronto. We would like to draw attention to our concerns about the design of the NAOMI trial and how its results are being interpreted. We would also like to propose an alternative solution to the heroin crisis in the Downtown Eastside. We believe that our proposed solution will be more cost-effective, safe and practical than the establishment of heroin or hydromorphone injection clinics.
The trial has not yet been published in a peer- reviewed journal and we have only reviewed its preliminary results. We are making our concerns public now because of the media attention the trial has generated, and because policy makers are already discussing the use of public funds for hydromorphone injection sites.
We wish to emphasize that our concerns with NAOMI are not ideological, but practical and clinical. We have been involved in the front lines of harm reduction treatment for many years and we remain committed to this approach to care. Also, despite our differences, we respect the scientific contributions of the investigators, and their hard work and dedication in completing such a complex trial. We also commend them for drawing attention to the treatment needs of this underserved population. Our concerns are summarized below.

Inclusion criteria
The rationale for NAOMI is that heroin users who were resistant to methadone treatment should be offered heroin treatment so they won’t have to purchase heroin from the street. The investigators did not define treatment resistance, and their inclusion criteria targeted early non-responders rather than treatment resisters. A patient might be defined as treatment-resistant if he or she continues to use heroin or drops out of treatment despite an optimal dose of methadone and the provision of counseling and support. Subjects were eligible for inclusion in NAOMI if they had two methadone treatment attempts, one of which was at least four weeks duration and at a minimum dose of 60 mg. A 60 mg dose is at the low end of the usual therapeutic range of 60-120 mg.
The methadone-only group had a treatment retention rate of 54.1%, which is consistent with the provincial average of 52% [1]. It seems probable that many of the subjects responded to the higher dose of methadone they received in NAOMI (mean 95.7 mg), suggesting that they were not treatment-resistant but had simply received inadequate doses in the community.
The preliminary report states that the median number of methadone treatment episodes for NAOMI subjects was three. Multiple treatment drop-outs only equates with treatment resistance if the patient received optimal treatment in at least one of the episodes. The investigators do not state the mean number of treatments; it is possible that many subjects only had one or two treatments. Although at least one of the treatment episodes must have been verified and have lasted for four weeks, any additional methadone treatments apparently were based on self-report and may have been attempts lasting for only a few days, brief hospital stays, methadone detoxification attempts, etc.

Intervention: methadone group
The mean methadone dose for the methadone-only group was 95.7 mg. This dose may be higher than what patients received in the community, but it is still low for a cohort of subjects who did not respond to previous methadone treatment. Controlled trials, meta-analyses and cohort studies have demonstrated that higher methadone doses are more effective than lower doses at improving treatment retention and reducing heroin use [2-10] [11, 12]. Several years ago, the mean daily dose of the methadone program at Centre for Addiction and Mental Health in Toronto was 92 mg [13], even though most patients at CAMH are prescription opioid users and presumably had lower levels of physical dependence [14]. The mean dose for methadone programs in a region of Norway was 111 mg; patients on doses of 105 mg or more had less heroin use than patients on lower doses [15] . A receiver operating characteristic analysis determined that a methadone dose of 100-140 mg per day was optimal in reducing illicit opioid use [16]. Patients attending higher-dose methadone programs (100-200 mg) have greater adherence to ARV treatment [17]. A prospective 10-year study in Israel found that prolonged treatment retention was associated with a dose of 100 mg or more [18]. Another study found that clinics with a maximum dose of 120 mg had twice the treatment retention rate as clinics with a maximum of 80 mg [19]. As one author concluded, "… the principles of rational therapeutics would suggest that IOT [Injection Opioid Therapy] should be seen as a ‘second line’ treatment modality limited to patients who … have adhered to conditions of effective methadone treatment for an extended period of time, yet continue to regularly inject illicit heroin…" (our emphasis) [66].
In future research, physicians prescribing methadone should be specifically trained to titrate the dose to achieve clear clinical objectives, i.e. relief of withdrawal symptoms and drug cravings for a full twenty-four hours, and elimination of regular heroin use. The Randomized Injection Opiate Treatment Trial (RIOTT) in the UK has incorporated optimal dosing into their trial methodology: "Methadone doses in excess of 80 mg (and generally > 100 mg) are encouraged (but not mandated) in this patient group…" [66]. Results of this trial have not yet been published. In our experience, methadone patients on doses of 120-140 mg or more rarely use heroin on a regular basis.
Intervention: Heroin group
The NAOMI subjects in the heroin arm received a mean dose of approximately 450 mg of pure heroin, plus 43 mg of methadone. Thus the methadone group’s mean dose was only 53 mg higher than the heroin group’s methadone dose. While we are not aware of any validated equivalence scales, in our experience 95 mg is not nearly as potent as 450 mg of pure heroin plus 43 mg methadone. The Spanish investigators used a dose equivalence formula to state that the two groups in their trial had equivalent opioid doses (105 mg methadone versus 275 mg heroin and 43 mg methadone) [20]. The RIOTT trial investigators stated that the heroin dose in the Netherlands study ( 65 mg of methadone plus 450 mg heroin) was equivalent to 200 mg of methadone [66]. We do not know the basis for these equivalence formulae, but assuming that they are accurate, then the methadone group in NAOMI would have had to receive a dose of 180 mg to be opioid-equivalent to the heroin group (almost double what they actually received).
These confounding factors - suboptimal methadone dosing, wide differential in opioid doses - make it difficult to draw conclusions from NAOMI and similar trials, and from the various secondary analyses that have arisen from them [21]. NAOMI and the other trials did not establish the superiority of heroin over methadone in cost-effectiveness or other outcomes; they simply proved once again that optimal opioid dosing is essential for opioid agonist programs of any type.
As far as we are able to determine, the pharmacological rationale for iv heroin treatment is that methadone-resistant patients will only stop illicit heroin use if they can continue to experience the euphoric effects of heroin in medical setting. We could find no evidence to support this position. Surveys of both methadone patients and out-of-treatment heroin addicts have identified a number of concerns about methadone treatment, for example, administrative fees, long waiting lists, fear of withdrawal, possible side effects of methadone, inflexible program rules, and unwillingness to be on methadone for ‘life’ [22, 23]. A desire for chronic heroin intoxication does not appear to be a major factor in their rejection of methadone treatment.
In our discussions with hundreds of heroin addicts, we have observed that fear of withdrawal is far more salient than a desire to get ‘high’, and in this respect methadone is a much more useful drug therapeutically than heroin. Experimental studies have shown that methadone in doses of 100 mg to 120 mg will completely relieve withdrawal symptoms for many hours [24, 25]. Because of its very slow onset of action and long half life, methadone in appropriate doses does not induce euphoria or sedation, and it attenuates the psychoactive effects of heroin [24, 25].
Besides optimal dosing, several strategies have been shown to be effective in addressing patients’ concerns about methadone treatment. One controlled trial found that 72% of patients who had dropped out of methadone treatment in the past 12 months returned after receiving two or more counseling sessions, compared to 53% in the comparison group [26]. In another study, 33% of 577 heroin addicts entered methadone treatment after receiving "free" treatment (no monthly fees), transportation assistance and rapid admission [27]. Another study found that physician attitudes towards abstinence versus harm reduction were correlated with treatment retention rates [28, 29].

Definition of treatment retention
The investigators classified subjects as "retained in treatment" if they a) were compliant with the treatment medication (heroin or methadone), b) were in a detoxification facility, c) were enrolled in a drug free program, or d) were abstinent at the 12 month mark. Except for (a), this definition of treatment retention is not very meaningful. Controlled trials have shown that detoxification has poor long-term outcomes and is significantly less effective than opioid agonist maintenance at maintaining heroin abstinence [30-34]. In the Australian Treatment Outcomes study, reduced heroin use at 36 months, continuous heroin abstinence over one year, and reduced rates of non-fatal overdose were all associated with maintenance treatment and residential rehabilitation, but not with detoxification [35-37]. One large study found that the risk of fatal overdose is significantly higher in the month after completion of any treatment, indicating that recently detoxified patients are at higher risk for overdose due to loss of tolerance [38]. Homeless, marginalized heroin users have higher failure rates than other substance users with outpatient detoxification [39]. The primary benefit of detoxification is that it may act as a ‘gateway’ for patients to residential treatment or to maintenance programs [40]. It will be important to review the investigators’ analysis of on-treatment retention, and the short and long term abstinence rates of patients attending detoxification facilities.

Outcome measures
It is likely that many subjects would have preferred to be in the heroin treatment arm, and this could have influenced results. For example, disappointed methadone subjects might have been more likely to drop out, or to report illicit heroin use. Furthermore, the main outcome measure for treatment response is the Addiction Severity Index. It is possible that subjects in the heroin arm would report their health and social status more favourably than patients in the methadone arm.
Thus, objective measures of outcome (urine drug screen results, hospitalizations and emergency room visits) will be useful for corroborating the study’s outcomes. Records from hospitals and medical clinics and from PharmaNet (the provincial prescription data base) would also be helpful. We understand that in NAOMI, urine drug screens were collected at 6, 9, and 12 months, and they were also collected clinically as per the BC College methadone guidelines. Urine drug screens are routinely used in addiction outcome studies for corroborating the subjects’ self reports of heroin and cocaine use. The RIOTT study used urine drug screens that detected papavarine metabolites, distinguishing illicit heroin from pharmaceutical heroin [66].

Safety of combining heroin and methadone
As far as we can gather from the preliminary data, there were 106 serious adverse events related to injection use. This includes 45 episodes of drowsiness, 13 overdoses requiring oxygen and naloxone, and seven seizures. The number of "non-serious" events, for example, drowsiness managed by observation alone, was not specified. There were apparently 61 serious adverse events in the methadone group, but an analysis of these adverse events has not yet been presented.
Clinically significant respiratory depression appears to be common in heroin-maintained subjects. In two European studies, almost half of the patients experienced respiratory depression, with markedly reduced O2 saturation and paroxysmal EEG patterns after receiving their usual heroin maintenance dose [41, 42]. Recurrent heroin intoxication can have long-lasting effects. In one study, 25% of heroin users had evidence of hypoxic and ischemic brain damage on autopsy [43]. Both methadone patients and heroin users have evidence of cognitive impairment on neurocognitive testing [12, 44-47].
Heroin-assisted treatment is highly unusual in medicine; we can think of no other treatment which is administered intravenously, several times per day, for an indefinite period in a non-hospital setting. Other injection treatments, such as insulin or anti-coagulants, are given subcutaneously which is a far safer route. Intravenous drugs bypass the liver, entering the central nervous system almost immediately. This causes sedation, which can result in trauma, aspiration and other adverse events. Benzodiazepine abuse is extremely common in heroin addicts [48], and benzodiazepines greatly increase the risk of heroin and methadone toxicity. Multiple intravenous injections also put patients at risk for a variety of infections, including deep tissue abscesses, endocarditis, osteomyelitis, and sepsis. Heroin addicts are at particularly high risk for infection because of immunosuppression, non-compliance with antibiotics, lack of awareness of early signs of infection, and difficulties with intravenous access.
The researchers have commented that whatever the risks of heroin substitution, it is safer than street heroin use [49]. This is no doubt true, but its safety relative to methadone must also be demonstrated, particularly since many if not most NAOMI subjects were not treatment-resistant and methadone remains a viable option for them. Therefore, it is essential that the safety of the intravenous heroin-methadone combination be rigorously evaluated before it is used in a clinical setting. As a start, the impact of heroin/methadone on oxygen levels, respiratory rate, heart rhythm and EEG needs to be measured.

NAOMI: Policy and research implications
We recommend the following:
1. Conduct safety studies
Additional studies are needed on the safety of intravenous heroin or hydromorphone plus methadone, including:
Monitoring and recording of the number of episodes of heroin-induced sedation and decreased level of consciousness, both on-site and in the community.
Monitoring a cohort of subjects on different doses of i.v. heroin or hydromorphone and methadone, for changes in oxygen level, heart rate and EEG.

2. Conduct further data analyses and interpretation
We recognize that the investigators have only released their preliminary results. Hopefully their more complete results will answer the following questions:
Outcome measures. What are the on-treatment response rates? That is, by the end of 12 months, how many patients were still on heroin treatment versus methadone treatment? Of patients who dropped out of treatment and attended abstinence-based treatments, what were the rates of heroin use and heroin abstinence over 3, 6 and 12 months? How many re-entered methadone treatment or attended residential rehabilitation? What are the objective measures demonstrating treatment outcome (health care utilization, urine drug screens)?
Prevalence of treatment-resistant heroin addiction. The NAOMI investigators have stated publicly that its subjects were highly resistant to methadone treatment and heroin is their only option. For example, in a recent news article, Dr. Schecter was quoted as saying: "Prior to NAOMI, all of the study participants had not benefited from repeated standard addiction treatments. Society had basically written them off as impossible to treat." The article goes on to say, "… the aim [of NAOMI] was to gather scientific evidence about the usefulness of prescribed heroin as a treatment for chronic addicts who have been helped by nothing else." (Reuters, October 24, 2008).
These statements should be treated with scepticism. AOMI’s preliminary data suggests that few heroin addicts in the community have received optimal treatment. The NAOMI team was contacted by 1,587 potential subjects. Of these, 1,006 were prescreened as ineligible, and 229 were found to be ineligible during full screening. Eighty-five percent of the pre-screened subjects were excluded because they had not met the inclusion criteria for prior methadone treatment.
In the original inclusion criteria, eligible subjects must have attended two methadone treatment attempts of at least four weeks at 60 mg or more. This was reduced to one treatment attempt, presumably because the investigators were having trouble recruiting enough subjects, even though their inclusion criteria targeted early non-responders rather than treatment-resistant patients. This suggests that the number of truly treatment resistant patients is likely very small. The NAOMI data should be reviewed to determine the subjects’ average duration and methadone dose in prior treatment attempts, whether they were in comprehensive treatment, and the number of subjects who met the objective clinical criteria for true treatment resistance.
Optimal methadone treatment. The data should be reviewed with respect to the treatment retention and response of methadone subjects at different doses of methadone. Was methadone dose correlated with treatment retention and heroin use?

3. Resist calls to create a hydromorphone injection clinic
Health Canada has refused to make heroin available to the investigators on compassionate release. Intravenous hydromorphone is pharmacologically similar to heroin, and NAOMI subjects could not distinguish between the effects of the two drugs. Since hydromorphone is legal and available in Canada, the investigators have already called for the establishment of a hydromorphone clinic. We feel that this would be premature, because the benefits and safety of hydromorphone injection have not been proven, the clinic will be very costly, and its establishment might increase hydromorphone diversion and abuse in the community.
Efficacy and safety of a hydromorphone injection clinic
In previous publications, advocates have stated that the effectiveness of heroin substitution has already been established, and one objective for NAOMI is to convince policy makers of the need for heroin clinics in North America [50]. Advocates have even suggested that providing heroin treatment is an ethical imperative; given its proven benefits, it would be unethical to force treatment-refractory patients to try a treatment that they have repeatedly failed in the past [51]. Unfortunately the controlled trials comparing heroin to methadone used designs very similar to NAOMI, with similar inclusion criteria, interventions and outcome instruments. They are therefore similarly flawed and difficult to interpret. As with NAOMI, subjects were early non-responders who were not given an adequate trial of comprehensive methadone treatment at an optimal dose. The mean methadone doses used in the control group were suboptimal, and (except perhaps for the Spanish study) the combined opioid dose was much higher in the heroin group than in the methadone group. The RIOTT study in the UK has attempted to overcome these biases through optimal methadone dosing (> 100 mg per day). Its results have not yet been published.
Table 1: Methadone and heroin doses in controlled trials
Study site Mean dose: Methadone group Mean dose: Heroin + methadone grouop
Germany 97-104 mg 440 mg H, 40 mg M
Spanish [20] 105 mg 275 mg H, 43 mg M
Netherlands [52] 75 mg 450 mg H, 65 mg M
UK [53] 99 mg 450 mg H, 8 mg M
NAOMI 96 mg 450 mg H, 43 mg M

b. A hydromorphone injection clinic will be costly. We are not certain of the per patient cost for NAOMI, but it will almost certainly be substantially higher than methadone treatment, which costs $5-6000 per patient per year. Heroin maintenance in Europe is estimated to cost about $16,000 Euros, or $21-22,000 per patient per year [21, 54]. Specially constructed injection rooms are required, and nurses and security guards must be on-site at all times. Intravenous hydromorphone is probably cheaper than heroin, but with the requirement for multiple daily supervised injections, it is still more expensive than once daily oral methadone that can be dispensed at any local pharmacy.
c. A hydromorphone injection clinic may adversely affect patients’ long-term recovery. A major goal of addiction treatment is to promote patients’ re-entry into productive activities and positive social relationships. Patients receiving comprehensive methadone treatment are often able to move away from drug-using neighbourhoods, reconnect with family and friends, and return to work and school. Methadone clinics and pharmacies are located throughout the province, and stable patients can receive take-home doses for up to one week at a time.
In contrast, patients on iv hydromorphone will find it exceedingly difficult to return to a productive life. They will be tied to one clinic in a high-risk neighbourhood. They will be unable to move from that location, even for a day. Their need for injections two or three times a day will make it difficult for them to work or attend school. They will spend much of their time with other clients in the clinic.
The investigators have stated that heroin patients who don’t wish to be tied to daily injections can "graduate" to either abstinence-based treatments or methadone. It would be important to know how many of the NAOMI heroin subjects voluntarily transferred to methadone, how many attempted abstinence-based treatments, and what their outcomes were. As mentioned above, abstinence-based treatments for heroin addiction have high relapse rates.
The clinic may increase hydromorphone diversion, injection and overdose in the community. The OPICAN study [65] has demonstrated that intravenous abuse of prescription opioids such as hydromorphone is a serious and growing problem in major Canadian cities. We are concerned that a hydromorphone clinic will legitimize the use of hydromorphone as an alternative to methadone and buprenorphine, and this will contribute to the growing problem of prescription opioid abuse and dependence in Canada. At least some physicians in Vancouver and elsewhere will conclude, with some justification, that if a highly respected academic clinic can prescribe hydromorphone, then they should be able to prescribe it for their own private patients. Opioid-dependent patients will soon realize that they can get a hydromorphone prescription if they explain to their physician that methadone treatment doesn’t work for them. While oral hydromorphone is safer than i.v. hydromorphone, it can easily be injected and sold on the street, and it can cause overdose. We note that only methadone and buprenorphine are approved by Health Canada for opioid agonist treatment. Both these medications are tightly regulated and prescribed only by physicians with special training. In contrast, hydromorphone is prescribed without restrictions in Canada, and medical regulators will be unable to monitor and limit its off-label use as an opioid agonist treatment.

The heroin crisis in the Downtown Eastside
In our opinion, the Downtown Eastside has a severe shortage of methadone treatment spots. In Canada, only an estimated one-quarter of opioid-dependent patients are in methadone treatment [55]. The situation may be even worse in the Eastside; one study found that heroin addicts in the Eastside were less likely to be in methadone treatment than other Vancouver opioid addicts [56]. The majority of methadone patients in Vancouver receive methadone treatment at privately run, for-profit clinics, which charge patients monthly fees. We hear repeated anecdotes of methadone care being abruptly terminated in cases where patients couldn’t continue to pay their fees. These clinics do not offer on site primary care, and counselor–patient ratios are too low to provide an effective standard of care. There are three government funded community clinics that provide comprehensive interdisciplinary care. These clinics have been operating at capacity for so long that potential patients no longer apply to get on waiting lists for treatment; the clinics don’t even keep waiting lists. Consequently we have no idea of the true demand for comprehensive treatment, but our clinical experience would suggest that the potential demand is high.

Practical and evidence-based solutions for the Downtown Eastside
We believe that clinicians, policy makers and researchers can do a great deal to improve the situation in the Downtown Eastside. All of the proposed solutions below are feasible and evidence-based, and are far safer and less expensive per patient than heroin or hydromorphone injection.

1. Ensure that heroin addicts have access to buprenorphine treatment
Numerous controlled trials have demonstrated that buprenorphine-naloxone (Suboxone) is effective in treating heroin addiction [57, 58]. Buprenorphine is a sublingual opioid agonist-antagonist with a duration of action of 1-3 days. Because its agonist effects plateau at high doses, it has a much lower risk of overdose than heroin, hydromorphone or methadone. As with methadone, it can be prescribed by family physicians and dispensed at community pharmacies. Unfortunately, Suboxone is not yet covered on the BC drug benefit plan, and there are no training programs in place for physicians, except an on-line course prepared by the drug company.
Establish several comprehensive methadone clinics for up to 1000 patients
The area desperately needs more comprehensive opioid agonist treatment clinics. The clinics should have the following features:
Physicians should be able to prescribe both methadone and buprenorphine.
Patients should be able to enter treatment quickly, within one or two days. There is evidence from controlled trials that "interim methadone clinics" (rapid entry into treatment with minimal counseling) have substantially higher treatment retention rates than waiting list controls [59].
The comprehensive methadone clinics should have strong clinical connections with facilities such as detoxification centers, hospitals and In-site, so that patients interested in treatment can receive it quickly and seamlessly. One study reported success with a coordinated transfer program from an acute detoxification facility to methadone treatment [60].
The clinic should be staffed by physicians who are knowledgeable about methadone dose titration and other aspects of addiction care.
The clinic should provide counseling, case management and outreach.
Primary care should be integrated on site with methadone treatment, to deal with the patients’ multiple physical and mental health problems [61, 62].
The clinic should provide specialty Hepatitis C and HIV care, including directly observed anti-retroviral therapy. Compliance with HAART (Highly Active Antiretroviral Therapy) is significantly increased if it is dispensed at a methadone clinic [63], particularly if the methadone dose is adequate [64].
We estimate that 600-1000 treatment spots would be needed to meet the immediate needs of the community. The clinic should be located at several different sites. Such a clinic will be expensive, but it will be much cheaper than the health care costs of untreated heroin addiction, and more cost-effective than a hydromorphone injection clinic.

Improve the quality of care in existing community methadone clinics
There is also an urgent need to improve the quality of care provided in existing community methadone clinics. Community methadone physicians need additional training and clinical support, and better compensation for counseling. The training should focus on treatment retention strategies, such as optimal dosing, counseling, sound clinic policies and case management. In addition, physicians should have access to the services of a counselor or case manager. Pharmacies also need better standards and training.

NAOMI had several methodological weaknesses that make its interpretation difficult. Its subjects included early non-responders, rather than treatment failures. The methadone subjects received sub-optimal methadone dosing, and their total opioid dose was substantially less than that of the heroin group. Patients were classified as retained in treatment if they attended detoxification facilities, even though the latter have high relapse rates. The study relied primarily on subjective measures. The heroin group experienced a significant number of serious adverse events, and the safety of the intravenous heroin-methadone combination has not been established in pre-clinical studies.
Given the limitations of the NAOMI study, the establishment of hydromorphone injection clinics in BC is premature. Such a clinic will be expensive and of unproven efficacy and safety, and it may result in hydromorphone diversion and injection in the community.
There are a number of cost-effective and practical strategies that will address the heroin crisis in the Downtown Eastside. We recommend that comprehensive methadone and buprenorphine treatment clinics be established as soon as possible, with 600-1000 treatment spots. The clinic should have strong connections with In Site, local emergency departments and detox centers, so that heroin users can have immediate and seamless access to methadone treatment. The clinics should be staffed by physicians experienced at methadone dose titration. Counselling, outreach and case management should be available. Primary medical care should be provided on site, as well as specialized treatment for HIV and Hepatitis C. In addition, community methadone providers should receive extra training, appropriate compensation for counseling, and support from addiction counselors and case managers. Pharmacists also need extra training and support.

1. Anderson, J.F. and L.D. Warren, Client retention in the British Columbia Methadone Program, 1996-1999. Can J Public Health, 2004. 95(2): p. 104-9.
2. Faggiano, F., et al., Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev, 2003(3): p. CD002208.
3. Caplehorn, J.R. and J. Bell, Methadone dosage and retention of patients in maintenance treatment. Med J Aust, 1991. 154(3): p. 195-9.
4. Strain, E.C., et al., Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial [see comments]. Jama, 1999. 281(11): p. 1000-5.
5. Amato, L., et al., An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat, 2005. 28(4): p. 321-9.
6. Dickinson, G.L., et al., A six-year evaluation of methadone prescribing practices at a substance misuse treatment centre in the UK. J Clin Pharm Ther, 2006. 31(5): p. 477-84.
7. Farre, M., et al., Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis. Drug Alcohol Depend, 2002. 65(3): p. 283-90.
8. Kamal, F., et al., Factors affecting the outcome of methadone maintenance treatment in opiate dependence. Ir Med J, 2007. 100(3): p. 393-7.
9. Termorshuizen, F., et al., Prediction of relapse to frequent heroin use and the role of methadone prescription: an analysis of the Amsterdam Cohort Study among drug users. Drug Alcohol Depend, 2005. 79(2): p. 231-40.
10. Villafranca, S.W., et al., Predictors of retention in methadone programs: a signal detection analysis. Drug Alcohol Depend, 2006. 83(3): p. 218-24.
11. Maxwell, S. and M. Shinderman, Optimizing response to methadone maintenance treatment: use of higher-dose methadone. J Psychoactive Drugs, 1999. 31(2): p. 95-102.
12. Maxwell, S. and M.S. Shinderman, Optimizing long-term response to methadone maintenance treatment: a 152-week follow-up using higher-dose methadone. J Addict Dis, 2002. 21(3): p. 1-12.
13. Brands, B., J. Blake, and D. Marsh, Changing patient characteristics with increased methadone maintenance availability. Drug Alcohol Depend, 2002. 66(1): p. 11-20.
14. Brands, B., et al., Prescription opioid abuse in patients presenting for methadone maintenance treatment. Drug Alcohol Depend, 2004. 73(2): p. 199-207.
15. Kornor, H. and H. Waal, [Methadone dose, treatment duration and heroin use in drug-assisted rehabilitation]. Tidsskr Nor Laegeforen, 2004. 124(3): p. 332-4.
16. Hallinan, R., et al., Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis. Drug Alcohol Depend, 2006. 81(2): p. 129-36.
17. De Castro, S. and E. Sabate, Adherence to heroin dependence therapies and human immunodeficiency virus/acquired immunodeficiency syndrome infection rates among drug abusers. Clin Infect Dis, 2003. 37 Suppl 5: p. S464-7.
18. Peles, E., S. Schreiber, and M. Adelson, Factors predicting retention in treatment: 10-year experience of a methadone maintenance treatment (MMT) clinic in Israel. Drug Alcohol Depend, 2006. 82(3): p. 211-7.
19. Caplehorn, J.R., et al., Retention in methadone maintenance and heroin addicts' risk of death. Addiction, 1994. 89(2): p. 203-9.
20. March, J.C., et al., Controlled trial of prescribed heroin in the treatment of opioid addiction. J Subst Abuse Treat, 2006. 31(2): p. 203-11.
21. Dijkgraaf, M.G., et al., Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials. Bmj, 2005. 330(7503): p. 1297.
22. Peterson, J.A., et al., Why don't out-of-treatment individuals enter methadone treatment programmes? Int J Drug Policy, 2008.
23. Stancliff, S., et al., Beliefs about methadone in an inner-city methadone clinic. J Urban Health, 2002. 79(4): p. 571-8.
24. Donny, E.C., et al., Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction, 2005. 100(10): p. 1496-509.
25. Donny, E.C., et al., High-dose methadone produces superior opioid blockade and comparable withdrawal suppression to lower doses in opioid-dependent humans. Psychopharmacology (Berl), 2002. 161(2): p. 202-12.
26. Goldstein, M.F., et al., Evaluation of an alternative program for MMTP drop-outs: impact on treatment re-entry. Drug Alcohol Depend, 2002. 66(2): p. 181-7.
27. Booth, R.E., K.F. Corsi, and S.K. Mikulich, Improving entry to methadone maintenance among out-of-treatment injection drug users. J Subst Abuse Treat, 2003. 24(4): p. 305-11.
28. Caplehorn, J.R., L. Irwig, and J.B. Saunders, Physicians' attitudes and retention of patients in their methadone maintenance programs. Subst Use Misuse, 1996. 31(6): p. 663-77.
29. Caplehorn, J.R., T.S. Lumley, and L. Irwig, Staff attitudes and retention of patients in methadone maintenance programs. Drug Alcohol Depend, 1998. 52(1): p. 57-61.
30. Gruber, V.A., et al., A randomized trial of 6-month methadone maintenance with standard or minimal counseling versus 21-day methadone detoxification. Drug Alcohol Depend, 2008. 94(1-3): p. 199-206.
31. McCambridge, J., et al., In-patient detoxification procedures, treatment retention, and post-treatment opiate use: comparison of lofexidine + naloxone, lofexidine + placebo, and methadone. Drug Alcohol Depend, 2007. 88(1): p. 91-5.
32. Amato, L., et al., Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database Syst Rev, 2005(3): p. CD003409.
33. Mattick, R.P., et al., Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev, 2002(4): p. CD002209.
34. Caldiero, R.M., et al., Inpatient initiation of buprenorphine maintenance vs. detoxification: can retention of opioid-dependent patients in outpatient counseling be improved? Am J Addict, 2006. 15(1): p. 1-7.
35. Teesson, M., et al., The impact of treatment on 3 years' outcome for heroin dependence: findings from the Australian Treatment Outcome Study (ATOS). Addiction, 2008. 103(1): p. 80-8.
36. Darke, S., et al., Factors associated with 12 months continuous heroin abstinence: findings from the Australian Treatment Outcome Study (ATOS). J Subst Abuse Treat, 2005. 28(3): p. 255-63.
37. Darke, S., et al., Non-fatal heroin overdose, treatment exposure and client characteristics: findings from the Australian treatment outcome study (ATOS). Drug Alcohol Rev, 2005. 24(5): p. 425-32.
38. Davoli, M., et al., Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. Addiction, 2007. 102(12): p. 1954-9.
39. Silins, E., et al., Residential detoxification: essential for marginalised, severely alcohol- and drug-dependent individuals. Drug Alcohol Rev, 2008. 27(4): p. 414-9.
40. Teesson, M., et al., Outcomes after detoxification for heroin dependence: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Rev, 2006. 25(3): p. 241-7.
41. Stoermer, R., et al., Safety of injectable opioid maintenance treatment for heroin dependence. Biol Psychiatry, 2003. 54(8): p. 854-61.
42. Stohler, R., et al., Rapid cortical hemoglobin deoxygenation after heroin and methadone injection in humans: a preliminary report. Drug Alcohol Depend, 1999. 57(1): p. 23-8.
43. Andersen, S.N. and K. Skullerud, Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts. Forensic Sci Int, 1999. 102(1): p. 51-9.
44. Fishbein, D.H., et al., Neurocognitive characterizations of Russian heroin addicts without a significant history of other drug use. Drug Alcohol Depend, 2007. 90(1): p. 25-38.
45. Liu, H., et al., Disrupted white matter integrity in heroin dependence: a controlled study utilizing diffusion tensor imaging. Am J Drug Alcohol Abuse, 2008. 34(5): p. 562-75.
46. Mintzer, M.Z. and M.L. Stitzer, Cognitive impairment in methadone maintenance patients. Drug Alcohol Depend, 2002. 67(1): p. 41-51.
47. Prosser, J., et al., Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment. Drug Alcohol Depend, 2006. 84(3): p. 240-7.
48. Bleich, A., et al., Benzodiazepine abuse in a methadone maintenance treatment clinic in Israel: characteristics and a pharmacotherapeutic approach. Isr J Psychiatry Relat Sci, 2002. 39(2): p. 104-12.
49. Oviedo-Joekes, E. Heroin Assisted Treatment
in Canadian Society of Addiction Medicine. 2008. Vancouver.
50. Fischer, B., et al., Heroin-assisted treatment (HAT) a decade later: a brief update on science and politics. J Urban Health, 2007. 84(4): p. 552-62.
51. Small, D. and E. Drucker, Policy makers ignoring science and scientists ignoring policy: the medical ethical challenges of heroin treatment. Harm Reduct J, 2006. 3: p. 16.
52. van den Brink, W., et al., Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. Bmj, 2003. 327(7410): p. 310.
53. Haasen, C., et al., Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry, 2007. 191: p. 55-62.
54. Blanken, P., et al., Matching of treatment-resistant heroin-dependent patients to medical prescription of heroin or oral methadone treatment: results from two randomized controlled trials. Addiction, 2005. 100(1): p. 89-95.
55. Popova, S., J. Rehm, and B. Fischer, An overview of illegal opioid use and health services utilization in Canada. Public Health, 2006. 120(4): p. 320-8.
56. Callon, C., et al., Barriers and facilitators to methadone maintenance therapy use among illicit opiate injection drug users in Vancouver. J Opioid Manag, 2006. 2(1): p. 35-41.
57. Barnett, P.G., J.H. Rodgers, and D.A. Bloch, A meta-analysis comparing buprenorphine to methadone for treatment of opiate dependence. Addiction, 2001. 96(5): p. 683-90.
58. Fiellin, D.A., et al., Treatment of heroin dependence with buprenorphine in primary care. Am J Drug Alcohol Abuse, 2002. 28(2): p. 231-41.
59. Schwartz, R.P., et al., A randomized controlled trial of interim methadone maintenance. Arch Gen Psychiatry, 2006. 63(1): p. 102-9.
60. Zaller, N.D., et al., Linkage to methadone treatment from acute opiate detoxification treatment. J Opioid Manag, 2006. 2(6): p. 341-6.
61. Millson, P., et al., Reduction in injection-related HIV risk after 6 months in a low-threshold methadone treatment program. AIDS Educ Prev, 2007. 19(2): p. 124-36.
62. Millson, P.E., et al., Self-perceived health among Canadian opiate users: a comparison to the general population and to other chronic disease populations. Can J Public Health, 2004. 95(2): p. 99-103.
63. Clarke, S., et al., Assessing limiting factors to the acceptance of antiretroviral therapy in a large cohort of injecting drug users. HIV Med, 2003. 4(1): p. 33-7.
64. Raffa, J.D., et al., The impact of ongoing illicit drug use on methadone adherence in illicit drug users receiving treatment for HIV in a directly observed therapy program. Drug Alcohol Depend, 2007. 89(2-3): p. 306-9.
65. Fischer, B. et al. Changes in illicit opioid use across CanadaCan. Med. Assoc. J., Nov 2006; 175: 1385
66. Lintzeris, N. Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin
treatment versus optimised oral methadone treatment in the UK. Harm Reduction Journal 2006, 3:28