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An Open Letter to the FDA:
Office-Based Opiate Detoxification

Stewart Nightengale, M.D. Associate Commissioner for Health Affairs
Food and Drug Administration HFY-1, Suite 15-36 5600 Fischers Lane
Rockville, Maryland 20857

October 13th, 1998
(formatted for printing)

Dear Dr. Nightengale,

Thank you for inviting me to contribute my thoughts regarding the
issue of office-based opioid therapy (OBOT) and specifically on the
outpatient treatment of opiate withdrawal.

Detoxification has been a large part of my professional work and
continues to be a special interest of mine. At Smithers Addiction
Treatment & Research Center, we have done progressively more
outpatient detoxification procedures over the past few years,
including over 200 outpatient detoxifications from opiates using a
variety of protocols and regimens. I also have four years of
experience supervising an inpatient detoxification unit in Roosevelt
Hospital. More recently I have been working with the New York State
Office of Alcoholism and Substance Abuse Services (OASAS) consulting
on the development of Part 816 of the Crisis Service Regulations and
co-authoring a course and manual on the development and proper
implementation of Crisis Services, particularly outpatient
detoxification. Currently I am adding outpatient detoxification
services to an existing intensive day treatment program at St. Luke´s
Hospital Center in New York City.

This letter offers an analysis of the forces promoting the increasing
use of outpatient, rather than inpatient, treatment for withdrawal
from alcohol and other drugs. Methods of opiate detoxification and
medications used are reviewed. I conclude that proscription of all
opioid medications in the treatment of opiate withdrawal is medically
incorrect, ethically questionable, and socially counterproductive.
Finally, I describe a model of a regulatory process and structure,
developed by OASAS in New York, that responds to legitimate concerns
of abuse and diversion of medications to illicit use.

When OBOT is discussed it is usually office-based maintenance that is
under consideration. While outpatient detoxification of the opiate
dependent person can be seen as a subset of OBOT, it differs from
maintenance treatment in terms of treatment goals, pharmacological
agents employed, visit schedule, and time-frame of treatment. Those
considering policy and guidelines for opioid therapy in the treatment
of opiate dependence need to be aware of these differences and take
them into account to avoid perpetuating the confusion and
misunderstanding that surrounds this issue.

The goals of detoxification are to prevent major medical and
psychiatric complications of withdrawal, to provide humane treatment
and relief from the discomfort of withdrawal, to engage the patient in
treatment and to motivate him to continue in treatment post detox.
Once pharmacologically and behaviorally stable, the patient can be
more fully assessed and referred to the appropriate modality and
intensity of substance abuse treatment, be that methadone maintenance
or continuing abstinence-oriented treatment. Historically this
detoxification / assessment / referral was accomplished on inpatient
units, often situated in hospitals. This is changing in response to
scientific, economic, and political pressures. Scientifically,
research continues to demonstrate the safety and efficacy of
outpatient detoxification in properly selected patients, and national
patient placement criteria guiding this selection process have been
widely adopted (the American Society of Addiction Medicine´s Patient
Placement Criteria (PPC), New York State´s Level of Care for Alcohol
and Drug Treatment Referral (LOCADTR) criteria, and other similar
tools).

Economically, increasing financial oversight of medical decision-
making has intensified the push to provide the least expensive
appropriate care. As a consequence, outpatient detoxification is
becoming more widely practiced and is rapidly becoming the more common
practice. Politically, largely as a result of the economic pressure of
Medicaid costs on state and federal coffers, pressure is mounting to
do detoxification on an outpatient basis. For example, the New York
State Office of Alcoholism and Substance Abuse Services has convened
an expert panel of physicians, administrators and regulators, has
developed regulations governing the licensure of providers to do
outpatient detoxification, and has published clinical guidelines and a
training curriculum to help substance abuse treatment providers
properly assess and treat patients in need of detoxification using
outpatient techniques where appropriate.

A variety of medications are employed in the management of opioid
withdrawal, solely or in combination. Each has benefits and drawbacks.

The opioids: A long-acting, orally or sublingually active, Mu agonist
(such as methadone) can be used to stabilize the patient by completely
suppressing the opiate withdrawal syndrome. After stabilization is
achieved, a gradual reduction of dose over days to weeks keeps the
addict relatively comfortable while evaluation continues and an
abstinent state is achieved. The risks of opioid therapy include risks
of abuse and toxicity. Any Mu agonist has the potential for abuse,
though different opiates vary widely in their reinforcing properties
and abuse liability. When used properly in outpatient detoxification,
only very limited quantities of medication are prescribed at each
visit (generally only a one day supply), and only for a limited period
of time and this makes significant abuse of the medication very
unlikely. Opiates, generally, have low toxicity, and this risk is
similarly limited in outpatient detoxification regimens by the small
amounts and duration of the medication regimens.

Alpha-adrenergic blockers: Clonidine, used in low doses as a
centrally-acting antihypertensive agent, relieves some of the signs
and symptoms of the opiate withdrawal syndrome when used in high
doses. Its mechanism of action is suppression of the sympathetic
discharge of the locus ceruleus which is stimulated in opiate (and
other) withdrawal states. The autonomic signs and symptoms of
withdrawal are suppressed; craving, anxiety, bone pain, insomnia, and
myalgias are not relieved. Treatment of opiate withdrawal requires
high dose regimens, relative to the dosages commonly used in the
treatment of hypertension, and these can be complicated by potentially
very serious side effects, especially orthostatic hypotension (which
can adversely affect underlying cardiac or vascular disease), fatigue,
lethargy, and depression. Further, because symptom coverage is not
complete, other medications usually need to be added to clonidine
detoxification regimens, often in moderate to high doses.
Benzodiazepines are added to treat anxiety, insomnia and muscle
cramping; NSAIDS for pain; Lomotil for diarrhea; and so on. Each of
these medications, in turn, has its own side-effect profile with
benzodiazepines also having the potential for abuse and diversion.
Because of restrictive regulations regarding the use of opiates in the
treatment of opiate dependence, clonidine in combination with
symptomatic medication is the most common method of outpatient
detoxification.

Benzodiazepines: Benzodiazepines in high doses have been used as sole
detox agents. They are also used in very high doses (light anesthesia)
as part of various ultra-rapid regimens. More commonly they are used
in low to moderate doses as anxiolytic and soporific agents in
combination therapy with clonidine and/or propoxyphene and in rapid
clonidine-to-naltrexone regimens. Benzodiazepines in the high doses
used in clonidine detox protocols commonly cause drowsiness, problems
with attention and memory, and mild motor dis-coordination. They can
also cause or exacerbate depression. Finally, benzodiazepines can be
abused and there is some risk of diversion of prescribed medication.

NSAIDs: Commonly used for analgesia in clonidine detox regimens where
bone pain and myalgias are inadequately treated. Dosages are often in
the high-therapeutic range where gastrointestinal side effects are not
unusual. Because of the regulations regarding the use of opiates in
detoxification, and because of the confusion surrounding the
regulations, the most common method of outpatient opiate
detoxification is to use clonidine to suppress the autonomic
manifestations of opiate withdrawal, in combination with
benzodiazepines and perhaps other medications to relieve the pain,
craving, restlessness, anxiety and insomnia. That opioid medications,
which can safely and effectively relieve the entire symptom spectrum,
are not employed as part of outpatient detoxification regimens in
selected patients is unfortunate for several reasons:

1. Physicians are forced to use multiple drugs in high doses and
with a poor cumulative side effect profile where fewer drugs at lower
doses and lower iatrogenic complication rates would do; this is
medically and ethically incorrect. Not only does this increase the
medical risk of the procedure, it also increases the risk of abuse and
diversion; diazepam is at least as highly valued on the street as
propoxyphene.

2. The population with more severe dependency and more severe
withdrawal, for whom outpatient detoxification might otherwise be the
appropriate modality, will not be manageable in this way.

3. The outcome research and randomized trials of various medical
regimens are inhibited by regulations, restrictions, and fears of
prosecution and harassment. This research is sorely needed to
determine best clinical practice in this relatively poorly studied
arena.

4. The regulations regarding the use of opiates in detoxification
are imprecise and poorly understood, and there is serious and
widespread confusion over interpretation of the rules. For example,
opiates are not proscribed for the treatment of pain in opiate
addicts; can opiates be used for the treatment of pain during
outpatient detoxification? Does the proscription against the use of
opiates in the treatment of “narcotics addiction” refer to OBOT
(usually long term, high dose treatment, with the dispensing of
weekly or monthly amounts) or to short term use of very small (daily)
amounts of relatively less abusable opiates to facilitate
detoxification to abstinence? If it applies to both, is it reasonable
to address such different procedures, with such different risks, in
the same way? Physicians are forced to weigh rationale medical
practice against poorly defined regulations which have not been
updated to take into account the dramatic increase in outpatient
detoxification. This is unfair and can only lead to defensive medicine
and poorer clinical outcomes rather than to best medical practice.

The use of less abusable opiates, as part of a good outpatient regimen
(daily visits, only enough medication dispensed or prescribed to get
the patient to the next visit, daily BAC and urine toxicology, strong
compliance contracting) can be a beneficial part of the treatment in
several ways:

1. Lower doses of clonidine (0.1 – 0.5 mg /day versus 1.0 – 1.5 mg
/day) can be used, thereby reducing the morbidity and potentially
serious side effects of high doses of that agent.

2. Lower doses of benzodiazepines (diazepam 5 – 15 mg/day versus
30 – 60 mg /day) can be used, thereby reducing the risk of
oversedation and of potentially dangerous interaction with alcohol.
This also reduces the amount of benzodiazepine medication dispensed or
prescribed, thereby limiting the risks of abuse and diversion.

3. Judicious use of selected opioid medications may improve
outcomes by reducing both withdrawal severity and medication side
effects. This is a highly researchable area in which much more work
needs to be done in this area.

In this context, consider the use of propoxyphene (Darvon or Darvon-N)
as part of a clonidine detoxification regimen. Propoxyphene is an
analgesic intermediate in action between aspirin and codeine. It has
been widely used to control the symptoms of narcotic withdrawal.
Tennant, using Darvon N as the sole detoxification medication, treated
400 heroin addicts with a five day taper from 1400 mg to 600 mg
(higher doses than would be required as an adjunctive to clonidine).
He reported good results with minimal withdrawal symptoms after abrupt
discontinuation of Darvon, and patients remained alert and active
throughout the treatment.

Propoxyphene offers several advantages as an outpatient detox agent
(see Sidney Cohen, “Darvon N: Its Role in Opiate Addiction”, in The
Substance Abuse Problems, Vol I, Hayward Press, 1981):

1. Long-acting metabolites make propoxyphene a reasonable choice
pharmacologically.

2. Both salts of propoxyphene are safe in the doses used,
especially considering they will be used as adjunctive medication and
only for several days in most regimens. Recovery from overdose has
been documented following the ingestion of 6,500 mg of Darvon and
9,000 mg of Darvon N alone. The initial adjunctive daily dose of
propoxyphene for the stabilization of withdrawal rarely exceeds 650
mg.

3. Unlike most opioids, propoxyphene is considered to be
relatively dysphoric at higher doses and there is generally little
patient demand to increase the dose. It is not highly prized by
addicts, “Much of its non-medical use seems to be directed towards
reducing a heroin ‘habit´ or avoiding withdrawal effects of heroin…”
rather than as a ‘get high´ drug. Abuse has been documented (Tennant,
1973, reporting on American soldiers stationed in West Germany under
conditions of extreme accessibility) but seems to be very uncommon.

4. It has very poor solubility in water and injection of suspended
material is painful and sclerosing. Intravenous use will never be
popular.

5. Propoxyphene in combination with clonidine permits lower doses
of both medications to be used.

It is useful to think about what the federal regulation, which forbids
the use of opioid medications in addicts for the purpose of treating
their opiate addiction, aims to accomplish. What outcomes of the
treatment of opiate addiction did we fear enough to justify the
restriction of medical practice over a decade ago? One outcome to be
avoided is the exploitation of opiate addicts by venal physicians
profiting from controlling the supply of the needed medication.
Another valid and worthy goal is to limit the amount of opioid
medication diverted from legitimate to illicit markets. Fears of abuse
and fears of diversion are legitimate concerns that have led us to the
regulations.

These fears and concerns are better addressed by guiding practitioners
toward good medical practices than by making illegal the use of a
medication for a purpose for which it is medically the safest and most
effective treatment. New York State is taking this approach in the
great effort they have made to develop regulations with significant
expert provider input and in their outpatient detox training
curriculum. They have also published the “Guidance Document for
Medically-Supervised Crisis Services in an Ambulatory Setting” for
clinicians starting to practice outpatient detox. Another document,
soon to be published, is the training manual that accompanies the two
day course given by the State to newly licensed provider of ambulatory
detoxification services. In this way, through regulation and training,
New York´s Office of Alcoholism and Substance Abuse Services (OASAS)
has set a standard of community practice in that State. This standard
provides for the daily physical and laboratory examination of
patients, the use of standardized methods of assessment and the
application of clinical criteria in treatment planning, the dispensing
or prescribing only very limited amounts of withdrawal medication
sufficient for the interval to the next examination, and criteria for
discontinuing treatment. These standards address the legitimate
concerns regarding risk of abuse and diversion.

I submit that the setting of a community standard of care is the
appropriate province of regulation and that regulations can be
profitably applied toward this end. However, State or Federal
regulation is a very blunt and inappropriate tool to bring to bear at
the level of what particular medications physicians use and at what
particular dosages. If proscribing the use of opioid medication leads
to the increased prescribing of benzodiazepines, what has been gained
in terms of abuse / diversion potential? If proscribing the use of
opioid medication leads to increased morbidity consequent to the use
of higher doses of multiple other medications, is this a desirable
outcome?

I applaud CSAT and the FDA in their willingness to reconsider policy
regarding OBOT. I support the suggestion of ASAM (Dr. Callahan´s
article in the most recent ASAM News) that consideration be given to
permitting the use of opioid medications in the treatment of addiction
by addiction medicine specialists. Certainly physicians receiving
special training and certification in outpatient detoxification in a
program similar to that of the State of New York should be allowed to
use selected opioid medications in a limited manner in accordance with
set community standards of care. A similar course and certification
might be carried out on a national level using the structure ASAM has
developed for the training and certification of Medical Review
Officers.

There are many ways we could attend to the legitimate concerns
surrounding this issue without restricting appropriate, evidence-
based, practice and inhibiting needed research. Thank you for taking
the time to consider my thoughts on this important matter.

Sincerely,

..alex...

Alexander F. DeLuca, M.D., FASAM, 10/13/1988.
(Then, , Chief, Smithers Addiction Treatment and Research Center
Division Head, Department of Medicine, St. Luke´s / Roosevelt Hospital Center
Chairperson, 1998 ASAM Certification Review Course, and
Member, Physician Advisory Panel, OASAS (New York State)

Currently in private practice with Dr. Peter Szilagyi:
185 East 85th Street, Suite 1 New York, NY 10028
adeluca@doctordeluca.com

O) 212-289-1525
Fax) 212-289-0500

Bibliography:

From the Principals of Addiction Medicine, Second Edition, ASAM, 1998:

- Kasser C. L., Geller A., Howell E., and Wartenberg A. A. “Principles
of Detoxification”

- Stine S., Meandzija, B. and Kosten T. R. “Pharmacologic Therapies
for Opioid Addiction”

- Payte J. T. and Zweben, J. E. “Opioid Maintenance Therapies”

Center for Substance Abuse Treatment (1994). Detoxification from
Alcohol and Other Drugs, Treatment Improvement Protocol (TIP) Series,
Vol. 19, Department of Health and Human Services

Cohen, Sidney. “Darvon N: Its Role in Opiate Addiction,” in The
Substance Abuse Problems, Volume One, The Hayworth Press, 1981.

Fraser, J.D. and Isbell, H. Pharmacology and addiction liability of d
l and d-propoxyphene. Bull. Narcot. 12:9, 1960

“Guidance Document for Medically-Supervised Crisis Services in an
Ambulatory Setting (Part 816.7)”. New York State Office of Alcoholism
and Substance Abuse Services, 1998.

Jasinski D. R., Johnson R. E., Kocher T. R. Clonidine in Morphine
Withdrawal. Differential Effects on Signs and Symptoms. Arch. Gen.
Psych. 42(11): 1063, 1985.

Tennant, F.S., Rawson R.A., Miranda L. et al. Outpatient Treatment of
Prescription Opioid Dependence: Comparison of two methods. NIDA
Research Monograph, 43:315, 1983.

Tennant, F. S. Complications of propoxyphene abuse. Arch. Int. Med.
132:191, 1973.

Washton A. M., Resnick R. B. Clonidine for Opiate Detoxification:
Outpatient Clinical trials. Amer. Jour. Psych. 137(9): 1121, 1980.

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