Field of the Invention This invention relates to methods of rapidly detoxifying opioid addicts so as to relieve conscious symptoms, and more particularly, to methods of detoxification employing sedation and a narcotic antagonist while permitting the patient to be ambulatory within eight hours of beginning treatment.

Background of the Invention Heroin addiction is a growing healthcare problem in the United States.

The United States Department of Health and Human Services'Substance Abuse Branch issued a report in December of 1994 stating that the number of emergency department visits directly related to heroin use rose from 48,000 in 1992 to 63,000 in 1993, a 31 % increase. The rate of heroin-related episodes per 100,000 people rose 81 %, from 15 to 28 per 100,000, between 1990 and 1993. Upon breaking down the heroin-using population into ethnic groups and age groups, it has been demonstrated that all subsets have increased rates of use for this time period.

Human opiate detoxification has been in use for some time. More than 31,000 individuals of the Empire Blue Cross and Blue Shield subscriber base in New York were hospitalized at least once for opiate dependency between 1982 and 1992.

The majority of these individuals were working adults, and their principal reason for hospitalization was addiction treatment. Drug detoxification accounted for 96% of the admissions, and the length of stay ranged between five and ten days.

It is widely known that heroin addicts fear and loathe heroin detoxification. For the addict, withdrawal can be like having a massive panic attack, an acute case of Huntington's Chorea, a psychological shock syndrome, and a nasty flu, all rolled into one.

Even if the less than warm reception by addicts is discounted, the current method of detoxifying an individual from opiates is flawed in several respects.

First of all, it is extremely uncomfortable for individual patients. Second, it can take days, and even weeks, for treatment, and this treatment is very expensive when one considers the overall length of stay at a hospital. Third, it is not very effective. Early relapse is the rule rather than the exception.

In the 1980s, outpatient protocols were developed in an attempt to reduce expenses and to entice more addicts to receive treatment. In one particular therapy, a shortened five-day schedule was employed. On the first day, patients received a naloxone hydrochloride ("naloxone") challenge test at 9: 00 a. m., using 0.8 mgs of naloxone, and then were started on clonidine hydrochloride ("clonidine") premedication. Clonidine is a potent antihypertensive agent and stimulates adrenergic receptors in the brain, leading to reduced sympathetic nervous system output. Daily averages of medication were, for day two: clonidine 1.1 mgs and naltrexone 8 mgs; day three: clonidine 0.6 mgs and naltrexone 40 mgs; day four: clonidine 0.3 mgs and naltrexone 50 mgs; and day five: clonidine 0.2 mgs and naltrexone 150 mgs.

In 1988, Loimer et al. described an inpatient technique in which 12 hours after the patient's last dose of opiate, they were sedated with 100 mgs of the barbiturate, methohexitone. This was followed by further injections of 400 mgs of methohexitone and 10 mgs of naloxone. After the narcotic effect had worn off, 2 mgs of naloxone was given intravenously about 30-40 minutes later. This did not elicit any further withdrawal response. This study showed that the acute onset of withdrawal symptoms induced by naloxone in opiate addicts is blocked by barbiturates.

Loimer et al. in 1991 described another inpatient, technique for enabling patients to transfer quickly from methadone to naltrexone maintenance. In a study of seven patients, they induced acute methadone detoxification by using a 4 mg

bolus of intravenous naloxone ten minutes after intravenous sedation was started with 30 mgs of midazolam, a short-acting benzodiazepine. After the naloxone infusion was completed, the patients received repeated dosages of flumazenil, a benzodiazepine antagonist, until they were awake. Within hours, the patients tolerated full doses of naltrexone.

Loimer pointed out that conscious sedation with midazolam was safer than general anesthesia. The technique also suppressed withdrawal signs and symptoms. Loimer used intranasal naloxone to induct patients onto naltrexone.

Loimer further described in 1993 an inpatient technique using intranasal naloxone. Twenty opiate-dependent patients reported a mean daily heroin dose of 2.0 grams for at least 2 months prior to detoxification. Twelve hours after their last heroin use, all the patients were sedated with 60 mgs of oral midazolam.

Simultaneously, they received 0.3 mgs of clonidine and 5.0 mgs of ondansetron (a selective 5-HT3 receptor antagonist, generally used to prevent nausea and vomiting associated with cancer chemotherapy). Ten minutes later, oral naltrexone, 50 mgs, was administered. The patients typically were asleep fifteen minutes post-midazolam, at which time withdrawal was precipitated by 4 mgs of naloxone administered nasally as a spray. Naltrexone, 50 mgs/day, was continued for the next 2 days before discharge.

Loimer has reported that none of his patients showed severe withdrawal distress before detoxification. He has found that following the administration of naloxone, withdrawal distress was significantly higher than baseline levels at 30,45,60 and 90 minutes, but that there were no significant differences from the baseline on all subsequent measurements. Furthermore, he has reported that systolic and diastolic blood pressure and heart rate did not change significantly during treatment.

Legarda and Gossop in 1994 also described an inpatient technique enabling heroin addicts to undergo a rapid transition to naltrexone maintenance, now referred to as rapid opiate detoxification ("ROD"). Legarda belongs to the CITA group, which has been detoxifying heroin patients in Spain, Israel and Mexico under general anesthesia.

As in Loimer et al.'s 1991 report, Legarda and Gossop used intravenous midazolam (0.5-0.7 mgs/kg initially, then as a constant infusion) for sedation. In this study, however, patients received an initial dose of oral naltrexone, 50 mgs, immediately prior to the injection of midazolam, and did not receive any naloxone reversal while under sedation.

They also pretreated the patients with repeated oral doses of guanfacine (like clonidine, a centrally acting agent with alpha-2 agonist properties) 1- 2 mgs/hour. Oral doses of loperamide (4 mgs) and ondansetron (8 mgs) were given, to avoid diarrhea and vomiting during the detoxification procedure.

During the time they were sedated, the subjects'opiate withdrawal signs primarily were piloerection, sneezing and motor agitation.

Four hours after the sleep induction, the patients received a naloxone test (0.8 mgs IV), and then 12 hours later they received 50 mgs of naltrexone, both of which provoked no withdrawal responses.

While Dr. Loimer's initial barbiturate procedure has relieved patients of the conscious symptoms of withdrawal by administering general anesthesia simultaneously with a large continuous dose of a pure narcotic antagonist, he requires patients to be carefully monitored for 12 to 24 hours. This is because barbiturate anesthesia tends to accumulate and is not reversible, requiring patients to be watched for an extended period of time following the procedure. It also minimizes the options available to the physician if adverse conditions arise, such as severe respiratory suppression.

The use of the benzodiazepines, such as midazalom is completely reversible by antagonists such as flumazenil, an imidazobenzodiazepine derivative.

Flumazenil competitively inhibits the activities at the benzodiazepine recognition site on the brain's receptor complex. Unfortunately, if the patient is dually-addicted to heroin and benzodiazepines, such as Zanax, Halcion, or Valium, the use of flumazenil to reverse the effects of benzodiazepine anesthesia can cause seizures.

In a 1993 Spanish survey of 973 heroin addicts, 68% of the patients admitted to using benzodiazepines, and 43% admitted to using them on a daily basis.

It has been observed that heroin-dependent patients often use benzodiazepines in the

days and weeks prior to seeking treatment to help them sleep when they are trying to cut down on their own. These reported figures are believed to be conservative since addicts have no trouble concealing their benzodiazepine use from their treating physician, even when provided with a warning of adverse side effects.

The duration of action for flumazenil may also not be sufficient to eliminate the effects of benzodiazepines which are still present in the patient's blood and bile. This can lead to resedation, and requires extended periods of observation.

Of course, extended observation is usually associated with additional nights in a hospital and added expense.

Another recent problem that has developed in detoxifying heroin addicts is the occurrence of profuse diarrhea in patients during withdrawal. The problem becomes even more severe when patients are sedated during the procedure, since they have no bowel control.

Summary of the Invention Methods of detoxifying patients addicted to one or more opioids are provided by this invention. The methods include sedating the patient with an anesthetic agent, ventilating the sedated patient, administering a diarrhea suppressant to the patient and then detoxifying the patient by injecting an opioid antagonist. The patient is then revived from the effects of the anesthetic and discharged in an ambulatory condition within about eight hours of being sedated. Diarrhea is significantly controlled, preferably with the addition of octreotide acetate solution.

Definitions naloxone hydrochloride: 1-N-Allyl-7,8-dihydro-14- hydroxymorphinone hydrochloride; a potent antagonist of endorphins and narcotics, including pentazocine; devoid of pharmacologic action when administered without narcotics. naltrexone: 17- (Cyclopropylmethyl)-4,5-epoxy-3,14- dihydroxymorphinan-6-one; an orally active narcotic antagonist; devoid of pharmacologic action when administered in the absence of narcotics.

propofol: an oil-in-water emulsion of 1,6-diisopropylphenol, a hypnotic with rapid onset and short duration of action; used intravenously for induction and maintenance of general anesthesia. Also called 2,6-diisopropyl phenol. octreotide acetate: L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L- phenylalanyl-D-tryptophyl-L-Iysyl-L-threonyl-N-[2 hydroxy-I-(hydroxy-methyl) propyl-, cyclic (2-7)-disulfide; 2 R- (R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. It is commercially available as Sandostatin octreotide acetate injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in buffered sodium chloride for administration by deep subcutaneous (intrafat) or intravenous injection. opioid: opiates, synthetic narcotics. opiate: any preparation or derivative of opium, including heroin.

A Detailed Description of the Invention The present invention provides for rapid detoxification of opioid addicts, including those who are dually-addicted to opiates and benzodiazepines.

An outline of the preferred therapy will now be described as an overview. At the initial office visit, a staff member conducts a biopsychosocial interview. At this time, the procedure is explained in depth along with a description of what to expect after detoxification is complete. The importance of group therapy and a support person following therapy is explained to the patient.

A complete history and physical examination is conducted, with a particular attention directed to prior difficulties with anesthesia on the part of the patient or his or her family. In addition, the arms and legs of the patient should be inspected for adequate venous access. An informed consent form is reviewed and executed, and warnings are given concerning what the patient should expect from the procedure.

The sedation procedure preferably involves the use of a rapid sequence induction of anesthesia, in combination with a rapid-acting, intravenous anesthetic agent. Propofol is a preferred rapid-acting intravenous anesthetic agent. Propofol has

a half-time of the blood-brain equilibration of about one to three minutes.

Additionally, propofol is known to reverse its effects within minutes.

Discontinuation of recommended doses of propofol injection after the maintenance of anesthesia for approximately 1-10 hours results in a prompt decrease in blood propofol concentrations and rapid awakening in less than 20 minutes, and usually within about 10-15 minutes. This is a drastic improvement over barbiturate anesthesia which is known to take hours for complete reversal.

In addition to the induction and sedation agents, the patient is preferably administered a dose of curare and succinylcholine, an effective, inexpensive paralytic agent commonly used in an induction. Paralysis is desirable since it significantly decreases the incidence of vomiting, however, this requires ventilation since it is necessary to breathe for the patient. After paralysis is induced, it can be maintained with pavilion or norcuron until the therapy is complete.

The patient should also be intubated for protecting the airway. When inducing withdrawal in a patient, particularly a severe withdrawal through the use of a narcotic antagonist, vomiting is a frequent side effect. In order to prevent aspiration of this vomitus, with possible life-threatening consequences, a tube can be placed in the airway with an inflated cuff.

After the patient has been intubated and ventilated, a preferred propofol drip is initiated intravenously. The effects of this intravenous anesthetic agent can be completely eliminated merely by discontinuing its administration. This sedative is also safe to use with dually-addicted patients, such as those that have both heroin and benzodiazepine addiction. In the event that adverse pulmonary or respiratory effects occur during detoxification, the patient can be revived nearly immediately. This is not the case with conventional ROD procedures.

In addition to intubation, a nasogastric tube should be inserted into the stomach cavity of the sedated patient. This allows for the insertion of naltrexone, an oral pure narcotic antagonist during the procedure. It also permits the evacuation of the stomach at any time during the procedure, which tends to lessen the production of vomitus should the person regurgitate.

Following sedation and paralysis, the patient is administered an IV of naloxone initially in a dose of at least about 0.4 mgs. This basically initiates withdrawal, typically exhibited by piloerection and a transient elevation of blood pressure. It acts rapidly and is short-acting. Pharmacological antagonism occurs immediately. Evidence of the abstinence syndrome can sometimes be seen, and if any complications arise, the procedure can be abandoned in its early phase.

After withdrawal initiates, the naloxone dosage can be increased to about 12 mgs intravenously, or a smaller dose of a stronger or longer-acting antagonist, such as nalmefene or naltrexone can be administered. This large dose will rapidly strip all of the receptors of opiates.

At about three or four hours, the patient should be fully detoxed, and a maintenance dose of opiate antagonist can be administered. This can be made through oral therapy, for example, by naltrexone, or alternatively, as a subcutaneous injection, implantation or insertion under the skin of the patient with a time-released antagonist-carrier mixture. Preferred carriers could include starch, cellulose or polymeric substances. Such materials should be biodegradable within the human body, and can include, for example, rod-shaped, injectable time-released naltrexone dosages combined with a water soluble glass, or a polymer, such as cross-linked polysiloxane copolymers, ethylene-vinyl acetate, and polyurethanes. See U. S. Patent Nos. 5,141,748; 5,088,505; 4,957,119 and 3,887,699, which are hereby incorporated by reference. Such compositions can also include time-release agents, erosion rate modifiers, antimicrobial agents and surfactants. Alternatively, a mechanical device may be used to create a time-lapsed delivery of the preferred long-acting antagonist substances.

The antagonist maintenance therapy preferably continues to release a minimum therapeutic dose at least once every three days, at least for one week following the procedure. This dose should eliminate the mood-altering effects of any opiate that the patient takes, and will help to maintain sobriety while the patient seeks counseling.

The stomach may be evacuated to avoid any vomiting upon awakening the patient. Additional medications, such as cholestyramine or potassium, can be

injected to decrease diarrhea or correct electrolyte imbalances. Paralysis is reversed with a known regiment of a paralytic agent antagonist, and the propofol drip is terminated.

Further specific details of the therapy will now be described in the following example.

EXAMPLE I The patient disrobes and is placed in a hospital bed. A certified registered nurse anesthetist is introduced and reviews the pertinent anesthesia questions with the patient. IV access is established in a peripheral vein with one liter of lactated ringers solution. All subsequent medications will be administered through the intravenous tubing, minimizing needle sticks. A small amount of local anesthetic agent is administered intravenously. The patient is administered 2-3 mg of propofol for the purpose of relaxation. The patient is connected to blood pressure, pulse, pulse oximeter, respiratory, EKG, and end-expiratory COZ monitoring. (Defibrillator and all emergency drugs are immediately available).

The physician is present throughout the induction and administration of pure narcotic antagonists which is performed in conjunction with the CRNA. A propofol infusion is prepared and accessed to the patient (50 ml vial of 10 mg per ml).

Strict aseptic precautions are observed in preparation. A bolus injection of propofol (20 ml via of 10 mg per ml) is prepared and a dose of 2 mg per kg is injected.

Simultaneously, the propofol drip is commence at 100 micrograms per kg per minute (6 mg per kg per hour). The patient is ventilated, intubated and placed on the ventilator. Cricoid pressure is applied during the intubation. Vital signs are recorded every five minutes during induction of anesthesia and every 30 minutes thereafter for the remainder of the procedure. Pavulon 0.1 mg per kg bolus is injected initiating neuromuscular blockade. This facilitates ventilation and prevents vomiting. The patient is then administered Glycopyrrolate 2 mg IV. This atropine-like medication decreases the marked secretions that patients typically produce during withdrawal.

An orogastric tube is then placed and the stomach is evacuated. The patient is

administered naloxone 0.4 mg IV and observed for signs of withdrawal, i. e., piloerection and increased blood pressure.

Naloxone is used due to its short half-life. It will initiate the withdrawal sufficiently and still allow an opportunity to abandon the procedure even at this point.

The patient is then administered nalmefene 2 mg IV. This drug occupies approximately 50% more of the receptor sites than naloxone and has a longer half-life (10.8 hours).

The patient is then administered naltrexone 50 to 200 mg via the orogastric tube. This initiates the oral therapy with a long-acting agent.

Neuromuscular blockade is maintained with norcuron 0.08 to 0.1 mg per kg based upon the patient's response to peripheral nerve stimulation. After three hours, the stomach is again evacuated. Cholestyramine 8 mg is then administered via the orogastric tube. This is for the prevention of diarrhea. At the end of the procedure, approximately 3.5 hours after the induction, the propofol drip is discontinued. The neuromuscular blockage is reversed with neostigmine 2.5 mg and atropine 1 mg IV bolus. This will also decrease abdominal discomfort after the procedure.

The patient is extubated after the following criteria are met: (a) train of four on peripheral nerve stimulation, (b) swallowing, (c) responds appropriately to verbal stimuli, and (d) sustained head lift of six seconds. The OG tube is removed with the endotracheal tube. A medical alert bracelet or necklace is applied to the patient. After about one hour of observation, within which the patient is assisted in getting dressed, he or she is then assisted out to the car. The physician is present at the termination of the procedure and during extubation.

In the post-procedure phase, the patient is very tired, weak and lethargic, and sleep may appear restless accompanied by extensive yawning. Leg and back pains are usually minimal and are relieved by either hot baths or wet/hot compresses. It is essential that the patient take the naltrexone at least once a day, at least for the first week after the procedure. Instructions are again reviewed with the caretaker. Those instructions include what to expect in the post-procedure phase.

The caretaker is instructed to call the doctor upon arriving home. The caretaker is

provided with the following: 12 capsules containing phenobarbital 250 mg with clonidine 0.25 mg (these medications are administered for the relief of nausea, vomiting, abdominal cramps and insomnia as directed by the physician); one rectal suppository containing phenobarbital 500 mg with clonidine 0.5 mg; and a prescription for naltrexone 50 mg to be taken one daily, dispense 30. The caretaker is instructed to contact the physician upon arrival at home. Contact is then made by telephone between the caretaker and the physician according to the following schedule: every two to three hours on the first day, and every six hours on the second day. Thereafter, contact is made between the patient and/or caretaker and the physician and/or a staff member daily for one week; then every three to four days for one week, followed bi-weekly for two weeks and periodically thereafter.

Aggressive telephone support is given to encourage a connection between the patient and a 12-step recovery program. Guidance is available for obtaining a sponsor and attempts to communicate with the patient's sponsor are made in order to help facilitate the transition to a support group. Follow-up office visits are scheduled at weekly intervals for two weeks, then bi-monthly for two months, then monthly and as needed thereafter. Again, this is primarily to facilitate the transition to a 12-step recovery program support structure.

EXAMPLE II The patient disrobes and is placed in a hospital bed, having received a Medical Alert insignia. A certified registered nurse anesthetist performs the pertinent anesthesia history and physical examination.

IV access is established in a peripheral vein with one liter of D5-1/2 lactated Ringers. All subsequent medications will be administered through the intravenous tubing, minimizing needle sticks. A small amount of local anesthetic agent is administered intravenously. The anesthetic agent, Propofol, tends to cause a burning sensation during initial administration and this minimizes discomfort for the patient. The patient is connected to blood pressure, pulse, pulse oximeter, respiratory, EKG, temperature and end-expiratory COZ monitoring. (Defibrillator and all emergency drugs are immediately available). Intravenous access is establish. The

patient is administered 3-5cc of 1 % Lidocaine. This desensitizes the patient's vein prior to the administration of Propofol. The patient is administered 2 mg of Midazolam for its amnestic effect. The patient is administered 20-30 mg of Propofol for the purpose of relaxation and as a test dose. The physician is present throughout the induction and administration of pure narcotic antagonists which are performed in conjunction with the CRNA.

A Propofol infusion is prepared and accessed to the patient (50 ml vial of 10 mg per ml). Strict aseptic precautions are observed in preparation. A bolus injection of Propofol (20 ml vial of 10 mg per ml) is prepared and a dose of 2 mg per kg is injected. Simultaneously, the Propofol drip is commenced at 100 micrograms per kg per minute (6 mg per kg per hour). The patient is ventilated (pre-oxygenation with 100% 02), intubated and placed on the ventilator. Cricoid pressure is applied during the intubation. Vital signs are monitored continuously during intubation and throughout the remainder of the procedure. Pavulon 0.1 mg per kg bolus is injected initiating neuromuscular blockade after adequate airway and ventilation have been established. The patient is then administered Glycopyrrolate 0.2 mg IV. Odansetron 2 mg IV is added. This is an anti-emetic drug which ameliorates the vomiting frequently associated with withdrawal. An octreotide 200 micrograms IV is established. This alleviates the diarrhea and crampy abdominal pain associated with opiate withdrawal. The patient is then administered Naloxone 0.4 mg IV and observed for signs of withdrawal, i. e., piloerection and increased blood pressure.

Naloxone is used due to its short half-life. It will initiate the withdrawal sufficiently and still allow an opportunity to abandon the procedure even after withdrawal begins.

The patient is then administered Nalmefene 2 mg IV. This drug has a longer half-life (about 10.8 hours) than naloxone. It remains in effect while the oral Naltrexone is being absorbed. An orogastric tube is then placed and the stomach is evacuated. The patient is then administered Naltrexone (ReVia) 200 mg via the orogastric tube. This initiates the oral therapy with a long-acting agent. Neuromuscular blockade is maintained with Pavulon based upon the patient's response to peripheral nerve stimulation. After three hours, the stomach is again evacuated. The neuromuscular blockade is reversed with Neostigmine 2.5 mg and Atropine 1 mg IV bolus. At the

end of the procedure, approximately 3 hours after the induction, the Propofol drip is discontinued.

The patient is extubated after the following criteria are met: (a) Train of four on peripheral nerve stimulation; (b) Responds appropriately to verbal stimuli; (c) Responds appropriately to verbal stimuli; and (d) Sustained head lift of six seconds. The OG tube is removed. The endotracheal tube is removed. The patient is assisted in getting dressed and out to the car. The physician is present during extubation at the end of the procedure. The patient is then observed for one hour prior to discharge.

In the post-procedure phase, the patient is very tired, weak and lethargic, and sleep may appear restless accompanied by extensive yawning. Leg and back pains are usually minimal and are relieved by either hot baths or hot wet compresses. It is essential that the patient take the Naltrexone (ReVia) at least once a day, at least for the first week after the procedure.

Instructions are again reviewed with the caretaker. Those instructions include what to expect in the post-procedure phase. Telephone numbers are exchanged and verified; these numbers include the physician's office number, beeper number and emergency number. The caretaker is instructed to call the doctor upon arriving home. The caretaker is provided with the following prescriptions: Naltrexone (ReVia) 50 mg to be taken one daily, dispense #30 and refill p. r. n.

Clonidine 0.2 mg to be taken one every four hours, dispense #20 with one refill.

Octreotide 200 micrograms per ml to be taken one cc subcutaneously q. 12 hours p. r. n. diarrhea; dispense #5 pre-filled syringes with needles. Refill times one.

The caretaker is instructed to contact the physician upon arrival at home. Contact is then made by telephone between the caretaker and the physician according to the following schedule: Every two to four hours on the first day. Every six to twelve hours on the second day. Thereafter, contact is made between the patient and/or caretaker and a doctor or a staff member daily for one week; then every three to four days for one week, then weekly for two weeks and periodically thereafter. We give aggressive telephone support to encourage a connection between the patient and a 12-step recovery program. We try to give guidance in obtaining a

sponsor and attempt to communicate with the patient's sponsor in order to help facilitate the transition to a support group.

Patients are evaluated according to the Short Opiate Withdrawal Scale (SOWS) by Michael Gossop during the recovery period, at 24 hours, and at 48 hours.

Follow-up office visits are recommended for two weeks, then bi-monthly for two months, then monthly and as needed thereafter. Again, this is primarily to facilitate the transition to a 12-step recovery program support structure.

From the foregoing, it can be realized this invention provides improved ROD procedures capable of being safely reversed even in the instance where the patient is dually-addicted to benzodiazepines and heroin. The present invention preferably takes advantage of the fast-acting aesthetic ability of propofol, and uses other techniques, such as paralysis, in rendering the detoxification process almost completely without symptoms. Although various embodiments for these therapies have been illustrated, this was for the purpose of describing, but not limiting the invention. Various modifications, which will become apparent to one skilled in the art, fall within the scope of this invention described in the attached claims.

It has also been determined in accordance with this invention that a GABAB agonist will relieve the spasticity, i. e., muscle twitching and spasms as well as the yawning and stretching associated with precipitated opiate withdrawal.

Furthermore, with using a GABAB agonist there has been shown a marked decrease in nausea and vomiting associated with the opiate withdrawal. Thus, the use of BACLOFEN (Lioresal), a GABAB agonist is preferably incorporated in the inventive precipitated withdrawal procedures. This drug can also be used to alleviate symptoms associated with other methods of opiate withdrawal. The GABA agonists can be administered virtually at any time before, during or after the inventive procedure. For a detailed discussion of GABA agonists and the use thereof, reference is made to U. S.

Patent No. 5,719,185, the entire disclosure of which is incorporated by reference herein.

Naltrexone (NTX) is a potent narcotic antagonist which works by blocking opiate receptors. Oral doses are biologically available and can provide

effective opiate blockage for up to three days. There is essentially no agonist activity, and side effects from the drug itself have been minimal.

Naltrexone was discovered in the 1960s and evaluated at some length in the 1970s. It appeared to have great promise as an adjunctive therapy in the opiate detoxification process. Although some success with NTX has subsequently been reported with relatively"controlled"population such as prisoners. But it has not lived up to its original promise. There appear to be two major reasons for this sub-optimal success. First NTX cannot be given until a patient is fully detoxified from opiates. Is NTX ingestion by an active user will precipitate sudden and violent withdrawal.

Second, use of oral NTX as an adjunct in the post-withdrawal phase requires regular dosing. An addict who misses or avoids his or her oral dose for over three days will once again be susceptible to the effects of opioids.

Early recognition of the issue of compliance with oral NTX after detoxification led to some initial work in the development and evaluation of slow- release subcutaneous depot NTX (DNTX) preparations, but the surge of interest apparent in the 1980s has not yet led to a published study demonstrating clinical utility with a large patient population. Thus described herein is a novel clinical experience with subcutaneous DNTX preparations and dosing which are different from those described in the earlier literature.

Patients are initially detoxified under anesthesia, with propofol the principle anesthetic. After induction with the propofol, patients are intubated and paralyzed. Withdrawal is then effected via administration of opiate receptor blockade with opiate antagonists. Initial subcutaneous pellet insertion of opiate antagonists usually occurs before a patient awakes from anesthesia. For those patients who received subsequent pellets, the insertion is usually performed under local anesthesia using 2% lidocaine with epinephrine.

EXAMPLE III All patients described herein were treated with pellets of NTX mixed with pharmacologically accepted excipients and compressed into a cylindrical form.

The first 83 insertions were of eight 75 mg pellets (600 mg of NTX). Each pellet was a cylinder 3 mm in diameter and 9 mm high, and the series of 8 pellets was inserted via a trochar with a suture to close the insertion site. This procedure may have led to breakage of pellets during insertion, and it is thought that greater dosage might have longer efficacy. For the 567 insertions, DNTX was changed to a single pellet which contained 1000 mg of NTX in a cylinder 12.5 mm in diameter 9.5 mm high, requiring a larger incision for placement.

The first NTX pellets were inserted into the subcutaneous tissues of the proximal arm after a small incision. As clinical experience with subcutaneous inflammatory or infectious events became evident, the insertion procedure evolved; four changes were made. First, all pellets were irradiated in order to sterilize them prior to implantation. Second, the insertion site was changed from the forearm to the abdomen. Third, suture material was changed from silk or staples to an absorbable suture material, Rapide (Ethicon, Somerville NJ). Fourth, in the last 492 cases (with 1000 mg pellets), a 3.5 cm tunnel was created under the dermis such that the pellet did not lie directly below the incision line.

The assay of efficacy was also changed during this clinical experience.

(See below.) Initially, serum NTX levels were monitored, but results as obtained from commercial laboratories appeared to be quite variable and not to coincide with clinical efficacy. The assay was therefore changed to a classical clinical assay of efficacy, direct opiate challenge. Fentanyl, a narcotic agonist more potent than morphine, was used as the challenge agent.

RESULTS This report covers 650 separate implantation procedures. The initial 83 implantations involved 600 mg of DNTX in 8 pellets. The population consisted of 71 patents, 57 men and 14 women with a mean age of 34.8 years (range, 20 to 55).

Eight of the patients had repeat procedures, with two implantations in 7 cases and six successive implantations in one case. The last 567 implantations were 1000 mg pellets placed in 410 patients, 306 men (mean age 35.3 with range 19-54) and 104 women (mean age 32.1 with range 17-50). This represents the first twelve months of experience with the 1000 mg pellet (from November 1996 to November 1997). In this group, 312 patients underwent a single implantation, 60 patients underwent two implantations, 22 three, 12 four, 3 five, and 1 patient had six successive implantations.

The first assay of clinical efficacy involved serum drug level testing.

Both NTX and its active metabolite, 6-beta-naltrexol, were assayed in patients who consented to assays. Twenty-four patients receiving the 600 mg pellets had levels drawn, with one level drawn in 17 patients, 2 levels in 4 patients, 3 levels in 2 and 4 levels in one. Twelve patients receiving the 1000 mg pellets had levels drawn, with one level in 8 patients, 2 levels in 2 patients, 5 levels in one patient, and 10 levels in 1 patient. The drug levels are presented in Figure 1A for the 600 mg pellets and 1B for the 1000 mg pellets. There appeared to be no consistent systemic levels. Most importantly, the drug levels did not correlate with clinical experience; many patients with no measurable drug levels anecdotally reported resistance to any effect of self- administration of narcotics. Specifically, no patient reported any response to street opiates within the first 30 days after implementation.

Because of the problem with NTX and 6-beta-naltrexol assays, the test of efficacy of DNTX was changed to a clinical assay using a potent opiate agonist, Fentanyl. Five cc (250 mcg) of Fentanyl were used for each challenge procedure.

Fifteen changes were performed, all on patients who had received the 1000 mg of DNTX. The results are presented in table 1. Of the fifteen challenges, 9 were given to men and 6 to women. The mean age of the patients being challenged was 34.5 with a range of 19 to 39. Challenges were performed as early as 21 and as late as 70 days

after implantation of the 1000 mg pellet. As can be seen, there were no significant changes in pupillary size or respiratory rate despite the significant narcotic load. In patient nine, there was a subjective impression of slight pupillary change which, if present, was too slight to be reflected in a change in measured pupillary size. The most significant adverse event after Fentanyl administration was what appeared to be a vasovagal response in patient five which was short-lived and not accompanied by evidence of opiate intoxication.

Phone contact was possible with 293 of the patients who received the 1000 mg DNTX. Forty-four (15%) noted an inflammatory response in the subcutaneous area of the pellet. Of these, four were felt to have been infectious (1.3% incidence in the sample contacted). No patient required more than oral antibiotic therapy.

All patient tolerated the NTX well apart from the local tissue reactions described above; there were no complaints of side-effects which may have been related to systemic NTX levels.

DISCUSSION Presented herein is an extended clinical experience with a new type of subcutaneous NTX pellet. Implantation of this pellet is safe and usually well- tolerated. Initial NTX drug assay determinations were disappointing and appeared not to correlate with clinical experience. The most important finding arising from this clinical experience is that, using fentanyl challenge, clinical efficacy of DNTX has been demonstrated for up to 70 days after implantation of a single 1000 mg NTX pellet.

Fentanyl is a synthetic opioid with approximately 80 times the potency of morphine. It has the shortest duration of action of the available opioid analgesics, making it a good candidate for opiate challenge. The dose given was the pharmacologic equivalent of a 20 to 25 mg bolus of morphine, a dosage at which even active opiate users would be expected to have definitive physiologic responses.

The blockade against opiate effect exhibited by this DNTX preparation is potentially crucial. The highest relapse rate after detoxification occurs within the

month following detoxification, a time during which the patients described herein were refractory to opiate effect. Even attempts at opiate maintenance have high recidivism rates, with failure rates of 66% within the first month of treatment with high-dose levomethadyl acetate (LAAM), the best of the results reported in a recent study. Note that DNTX did not prevent experimentation with street drugs post- detoxification. If did prevent the drugs from having a significant physiologic effect, which prevents early re-addiction and allows a longer period rehabilitation.

The lack of correlation of drug levels with clinical findings was disappointing. Prior research studies of NTX dosing and metabolism have used drug levels effectively. The problem may have occurred with some degradation after collection or may have been due to lab processing. The labs used were commercial laboratories, not labs with a research interest in NTX.

In this study, it has been chosen to describe an extended clinical experience with subcutaneous NTX pellets rather than an end point. This lead to obvious weaknesses; the transition point at which each change in technique was made is not definite in this retrospective review. While only the last 300 implantations could have been presented in this study, those treated with the 1000 mg pellet at a point when all technique changes had been made, it is thought that the process arriving at this dosage and methodology contains clinically relevant information.

The only complication of NTX implantation which occurred with frequency was inflammation at the insertion site, and this led to the changes in technique described above. As noted above, a local response at this insertion sites is still common (15%), although very few of the events (1.3%) appear to be infectious and none required more than oral antibiotic therapy and local soaks/dressings. Of note, earlier animal studies with a different DNTX preparation have demonstrated that individual animals exhibited non-necrotic inflammatory response which appeared to be caused by the NTX itself. The inflammatory response may even play a positive role in the effective slow absorption over time reflected in the clinical efficacy of the DNTX preparation. That no systemic side-effects were reported is not surprising, as drug levels from the slow release of the subcutaneous NTX would be significantly

lower than those obtained by oral administration, and even orally administered drug has minimal side effects.

NTX is a potent and effective narcotic antagonist. After it aroused clinical excitement in the early 1980s, its potential efficacy met two major barriers.

First, patients have to be completely detoxified before NTX can be started, as dosing an active opiate user will lead to full-blown and accelerated withdrawal. Second, although it is orally available and has a longer duration of effect than the other available narcotic antagonists, NTX still needs to be given orally a minimum of three times a week, making compliance an issue. It is thought that the first of these two issues has a solution in the use of accelerated opiate detoxification under sedation or anesthesia. The development of long-acting subcutaneous NTX deposition as presented herein represents a viable solution for the second issue.

The development of a subcutaneous, slow-release form of NTX is known. As mentioned, several articles in the early 1980s described the manufacturer of NTX-containing pellets and of their biological release in both animals and human beings. This form of subcutaneous NTX was demonstrated to give a promising release profile with reasonable drug levels, and prolong resistance to opiates in both human and non-human subjects after implantation was demonstrated. Work with these preparations tapered off after the mid-1980s. It is thought that reasons for this tapering are, first, the system used for the preparation of pellets in those studies was protracted and extremely expensive; second, high doses of NTX apparently were not achieved by the methods described; and third, incomplete detoxification made it difficult to initiate NTX therapy. The present invention presents the first extended clinical experience with any DNTX preparation.

In contrast to the difficult and expensive preparation involved in earlier efforts, the pellet preparation method used for this study is quite simple. Note that recommended oral NTX maintenance regimen is 50 mg a day and that the subcutaneous pellet of 1000 mg will last for at least 30 days. Thus approximately two-thirds of the number of milligrams is required for the subcutaneous pellet, a factor which could displace substantial manufacture and pellet placement costs.

Further, in accordance with the present invention, maintenance of chemical sobriety with DNTX is far more convenient than maintenance of opiate dependence with a long-acting opiate such as methadone.