Rebuttal to JAMA Article

In an article appearing in JAMA in August 2005 entitled, “Anesthesia-Assisted vs Buprenorphine- or Clonidine-Assisted Heroin Detoxification and Naltrexone Induction,” authors Collins, Kleber, Whittington and Heitler conclude that “rapid opioid detoxification with opioid antagonist induction using general anesthesia has emerged as an expensive, potentially dangerous, unproven approach to treat opioid dependence”.  On closer look at their methods, results, and interpretations it is clear that this is in fact not the case at all.  They further claim that their own data “do not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction.”  This article will show that the authors failed to demonstrate the conclusions they claim and that in fact when performed using strict guidelines and with appropriate safeguards, anesthesia-assisted rapid opiate detox is a safe, cost-effective method that is a valid alternative for many patients with opiate addiction.
Using the Waismann Method, the procedure as done in our center is safe and effective and addresses the need for a rapid, humane, and well-tolerated opiate reversal method.  Our results for our more than 1700 patients using our method (The Waismann Method of rapid detox) demonstrate no life-threatening adverse events during the procedure.  One patient had aspiration pneumonia and recovered completely with antibiotics and chest physiotherapy.  At 12 months following Anesthesia-Assisted Detox, nearly 70% of our patients remain opiate free, as per Waismann Institute reports (unpublished), based upon patient self-reporting.
As the authors of the Collins, Kleber, et al paper correctly point out, addicted patients and the general public feel a sense of “desperation” about the treatment of opiate dependence.  Traditional methods have failed to provide a humane, well-tolerated and effective means of reversing opiate dependence.  Drop out rates from traditional methods are extremely high, up to 30% in some reports (Scherbaum).  Success rates as defined by long-term abstinence rates after detoxification are disappointing.  Patients and their families are eager for the availability of a safe, short, comfortable and effective method of detoxification.  We agree that it is imperative that treatment modalities such as anesthesia-assisted opiate detox are subject to rigorous review and are held to the highest standards, however, we question the methods and conclusions of the authors of this study.
With the goal of trying to compare the safety and efficacy of anesthesia-assisted rapid detox with other medication based methods of rapid opiate reversal, the authors of the 2005 study compared anesthesia-assisted to buprenorphine-assisted detoxification and to detox with clonidine alone.  Given the unrestricted grant from Reckitt Benckiser, the manufacturer of buprenorphine, provided to Dr Kleber, who was one of the principal investigators of the study, it is hard to imagine an unbiased approach to the study outcome.
For the study a total of 105 heroin-dependent patients were randomized into three inpatient withdrawal treatment groups.  Patients were initially included if they simply reported “general good health” and could be classified in the American Society of Anesthesiologists physical classification status I or II, ie “otherwise healthy, no other medical problems” for class I, or “a chronic medical condition that is well-controlled, eg, hypertension, diabetes, asthma, for class II”.  It was only after three patients had serious complications during anesthesia assisted detox that inclusion and exclusion criteria were more appropriately defined and restricted.
Patients in the study were randomized into three treatment arms:  Patients in the anesthesia-assisted group were maintained under anesthesia for 4-6 hours on the morning of day 1 after a pre-anesthesia dose of clonidine (0.3 mg) and were given a 50 mg dose of naltrexone induction during anesthesia, as well as nalmefene 4 mg over 30 minutes. This was followed by maintenance doses of naltrexone beginning the following day (50 mg daily); the buprenorphine group received an initial sublingual buprenorphine dose on day 0, and began naltrexone induction on day 2; the clonidine group was given no anesthetic agents and no opiate antagonist at all during their inpatient phase and did not begin naltrexone until day 7.  Following hospital discharge, all patients were followed for 12 weeks.  During the outpatient phase of the study for all three arms, every patient was given daily naltrexone (50 mg) and twice weekly relapse-prevention psychotherapy.  At these visits, urine samples were collected for toxicology.
The study reported 3 serious adverse events occurring in the anesthesia arm of the study.  However, a closer look fails to identify a causal relationship between the Anesthesia-Assisted Opiate Detox and the event. One patient had severe pulmonary edema and aspiration pneumonia necessitating reintubation and intensive care unit management for 5 days.   The patient subsequently admitted a prior history of “several prior complicated pneumonias and of possible obstructive sleep apnea”.  Following this experience, the investigators recognized that these conditions must be exclusionary for anesthesia-assisted detox.   In addition, with appropriate anesthesia monitoring and maintenance of patient ventilation, severe pulmonary edema should not occur.  This was not a complication of Anesthesia-Assisted Rapid Opiate Detox, but rather one of anesthesia technique and monitoring.  A second patient developed suicidal ideation requiring psychiatric hospitalization 5 days after anesthesia and subsequently revealed a prior diagnosis of bipolar disorder.  Again, not only was this occurrence not a complication of the Anesthesia-Assisted Rapid Detox, but significant psychiatric history was then recognized as sufficiently exclusionary for undergoing the procedure.  In a third adverse event, an insulin-dependent diabetic presented a difficult glucose management problem post-anesthesia, delaying hospital discharge by one day, and then developed diabetic ketoacidosis (DKA) two days following discharge.    A prior history of DKA was elicited that had previously been concealed.  Once again, this experience led the investigators to revise their exclusion criteria to specifically exclude patients with glucose greater than 160 or with any history of insulin-dependent diabetes.
Clearly, if rigorous inclusion/exclusion criteria had been applied from the start, each of the adverse events reported in the study would have been avoided.  When patients are carefully screened and AON is utilized only for a select population of otherwise healthy individuals, the method is clearly a safe alternative.
Further, in each of these cases, the adverse event was not caused by the Anesthesia-Assisted Opiate Detoxification.  Clearly, the psychiatric complication of the bipolar disorder occurring 5 days after anesthesia was not the result of  Anesthesia-Assisted Rapid Detox itself but might have occurred given any circumstances.  The pulmonary edema and glucose derangements were not the results of the Anesthesia-Assisted Rapid Detox.  In our experience, not one patient of more than 1700 has had blood pressure abnormalities or hyper/hypoglycemia.
With our method, patients are placed under anesthesia using propofol and kept sedated for 45 – 60 minutes total.  This short duration using “light” anesthesia minimizes the risks of complications associated with the use of anesthetic agents.   In the anesthesia-assisted arm of the Collins study, patients were put under general anesthesia with propophol, isoflurane, and midazolam (a much deeper anesthesia) and paralyzed with vecuronium as needed, and then kept under general anesthesia for 4-6 hours   It is unclear why they were kept under anesthesia for so long, but clearly the more prolonged the time under anesthesia, the greater the risk of anesthesia-related complications.  Patients were only given 0.3 mg of oral clonidine prior to anesthesia induction, which is not enough to counter the noradrenergic hyperactivity associated with opiate withdrawal, and were given an excessively large, rapid dose of nalmephine (4 mg IV over 30 minutes).  The selection of these doses may explain the hemodynamic fluctuations faced by the investigators.     Using a slower administration of nalmephine over 60 minutes, rather than 30, and a dose of 1.5-2 mg rather than the 4 used in the study, we have found that patients tolerate the procedure extremely well, and have faced no such difficulty with hemodynamic instability.
For the purposes of the JAMA article, withdrawal severity was assessed by standard severity scales (SOWS, OOWS, and COWS).  Patients in the anesthesia group demonstrated unusually high withdrawal severity prior to the initiation of the procedure, which the authors attribute to anticipatory anxiety.  This is in contrast to our experience.  The authors then failed to demonstrate a consistent pattern of withdrawal severity with the three measurement tools selected.  It is hard to claim that  Anesthesia-Assisted Detox was not better tolerated than other methods of detox given this inconsistency.  Clearly, this needs to be evaluated further to demonstrate our firm belief that undergoing the most severe withdrawal symptoms under anesthesia is more comfortable than experiencing them while awake.
For the purposes of the study, patients were considered to have relapsed if opiates or any drug (including marijuana, benzodiazepines, barbiturates, and amphetamines) was found to be present in urine samples.    Patients were therefore considered relapsed if they remained abstinent from opiates but tested positive for other substances.  Looking just at the mean proportions of patients with urine samples positive for opiates, the authors claim no differences, but the anesthesia-assisted group appears better, with 0.54 compared to 0.62 and 0.73 for the buprenorphine and clonidine groups, respectively.  Overall their patient retention results were dismal for all three treatment arms.  Patients were considered “dropouts” if they relapsed to opiate dependence or missed two consecutive weeks of outpatient visits.  Interestingly, relapse to opiate use was determined by two urines positive for opiates.  We would consider any urine positive for opiates to identify opiate relapse.
The retention rate at 12 weeks was only 5 patients each (14%) for both anesthesia and buprenorphine-assisted groups and 2 patients (5.9%) for the clonidine group.  This is unusually poor and may reflect either unique factors of their method or excessively broad dropout criteria.  If patients did not follow through with their outpatient therapy visits they were then considered retention failures.  However, perhaps these individuals remained opiate-free and were dissatisfied with the therapy offered.  Without other information, it is impossible to consider them treatment failures.  By week three post hospitalization 50% of the patients were considered dropouts on the study.  Only 19 patients total of the original 106 enrolled in the study were considered retained at 12 weeks.  Rather than assuming all others were failures, perhaps there was something wrong with the rehab program offered, or perhaps there were other confounding factors.
As to be expected, the investigators report significantly higher naltrexone induction rates (defined as taking any dose of naltrexone) in the anesthesia-assisted and buprenorphine arms compared to the clonidine group, since the clonidine arm was not given any naltrexone until day 7. (94% and 73% vs 18%, respectively)  The 94% induction rate they report in the anesthesia group, which is not representative of the 100% rate that should have been cited, given that all patients who initiated anesthesia received their induction doses of naltrexone.  In contrast, patients in the clonidine and buprenorphine groups were able to quit after initiation but prior to completion of detoxification.  As the authors note, “a significant relationship existed between naltrexone induction at the full 50 mg maintenance dose and attrition, with those achieving full-dose induction at lower risk of dropping out”.  Put another way, 100% of anesthesia-assisted patients by definition will complete naltrexone induction, and therefore have a higher rate of treatment completion.  For naltrexone maintenance in the study, a dose of 50 mg daily was “recommended” on discharge from the hospital.  Our patients are provided with 12.5 to 25 mg for daily dosing, a dose that may improve compliance.
With such poor retention rates for their patients across all three treatment arms, and such a high rate of patients who were lost to follow up as well as the small population size in each study arm, it is hard to come to any clear conclusions at all from this study.   Our experience, with over 1700 patients undergoing ROD, has demonstrated a 70% sustained abstinence rate at one year, very different from the retention rates cited here.
We believe Rapid Opiate Detox to be a safe, effective, and appropriate alternative for many patients. Collins et al included only patients with heroin addiction.  The investigators did not address the population of individuals addicted to prescription opiate analgesics, and therefore their results can not necessarily be generalized to this population.  National Institute on Drug Abuse (NIDA) Director Nora Volkow has stated that up to 7% of patients who are prescribed opioid analgesics for chronic pain will become addicted.  It is estimated today that there are more than  4.7 million Americans dependent on prescription painkillers, which represents up to 2% of the US adult population overall.  (Substance Abuse and Mental Health Services Administration 2004, from NIDA website)   For this large (and increasing) population, we believe ROD is a valid, safe and effective alternative that was completely ignored by the authors of this paper.
In our patient population, the most common drug used was Oxycontin, with 23.2% of the patients reporting its use.  17.7 % reported Heroin use, Vicodin was reported by 15.7%, Methadone by 11.6%, Norco by 8.4%, and Hydrocodone by 5.3%. Several other opiates were reported each with fewer than 5% of patients reporting use.  In 2004 and 2005, 70-71% of individuals who underwent Rapid Detox with the Waismann Method stated that they were initially prescribed the drug by their physician, with 52 % of those with painkiller dependence reporting back pain as the initial reason for taking the drug.  (Waismann Method 2005 Opiate Dependency Survey)
It is possible that our results may be significantly better than those reported by others not only because our anesthesia methods are safer, but because our patient population is a uniquely motivated and well-supported one. This is a hypothesis worth evaluating. In the Collins study, heroin addicts were recruited and were paid $15 for their participation.  Patients were discharged from the hospital back into their starting environments, possibly including homelessness.  In contrast, our patients sought out  Anesthesia Detox and frequently self-referred to our center, and represent a more motivated group with social, financial and other support systems to aid them in their long-term abstinence.  We consider Anesthesia Detox to be not a cure for the disease of opiate addiction, but rather a reversal of opiate dependence that allows patients to return to productive lives and to take responsibility for their future sobriety.    The rewarding abstinence rates of 70% at one-year post-Anesthesia Assisted Detox is gratifying, but also reflect perhaps the strong support systems and financial resources that our patient population possesses.
Collins, et al, consider Anesthesia-Assisted Detox to be prohibitively expensive for use as a method of detoxification.  Admittedly, the $7,500 to $15,000 price tag they report is a large expense.  However, when compared to traditional methods of treatment for opiate addiction, Rapid Detox may actually be less costly.  Traditional methadone maintenance programs (MMTPs) for heroin and other opiate addicts substitute a legal, medically dispensed opiate (methadone) for the patient’s drug of use.  With MMTP patients remain opiate dependent, in contrast to the complete reversal of opiate dependence immediately following Rapid Detox.  Annual methadone maintenance was found to be approximately $4000/year in 1994 (Gold – ref Bradley CJ 1994), continuing over several years, not including the cost of ongoing counseling.  Often, MMTP treatment is a lifelong commitment, meaning decades of methadone expenditures.  An initial 2-3 years of methadone maintenance can cost the same as the one-time expenditure for Anesthesia-Assisted Opioid Detox, yet methadone maintenance may continue to drain resources for life.
Similarly, compared to inpatient detoxification or residential rehabilitation centers with costs as high as $30,000 for a one month stay, AON is a less expensive and less time-consuming alternative. Rapid opiate detox allows individuals to return to work or other productive activities in just a few days. Given the lack of evidence that these residential detox programs have any better outcomes, it is clear that AON is actually more cost effective.  Despite arguments against the high cost of AON, in fact, it may be more cost-effective in the long run than both long-term methadone maintenance or other traditional methods of detox.
In summary, in the Collins article, there is an inherent financial bias toward buprenorphine; anesthesia assisted patients in the study, in our opinion, were given far too little clonidine and too much nalmephine and kept under anesthesia for too long;  Patients were not given a choice of mode of follow-up therapy following discharge, (our patients are able to follow-up with any out-patient therapy they choose) which may have contributed to the extremely high dropout rates seen in the study; adverse events reported in the study not only would have been prevented if the inclusion/exclusion criteria had been rigorous from the start but were not directly the result of  Anesthesia-Assisted Opiate Detox at all.  In addition, the failure to include patients other than heroin addicts may have eliminated a higher functioning population predisposed to do better with this method.
Clearly, Anesthesia-Assisted Detox is a cost-effective, valid, safe, humane and effective method of opiate reversal that should be accepted and made available to a wider population of patients with opiate addiction.

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