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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


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.

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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.

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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.  

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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.  

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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.

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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.  
Then, (10/13/1988), Chief, Smithers Addiction Treatment and Research Center  
Division Head, Department of Medicine, St. Luke’s / Roosevelt Hospital Center Chairperson, 1998 ASAM Certification Review Course
Member, Physician Advisory Panel, OASAS

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


Email:   adeluca@DoctorDeluca.com
Phone:  212-289-1525 
Fax:     212-289-0500
   

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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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