WO2001076522A1

WO2001076522A1 - Maintaining abstinence after detoxification from opiate addiction

Info

Publication number: WO2001076522A1
Application number: PCT/US2001/011181
Authority: WO
Inventors: Clifford Gevirtz; Bennett Oppenheim
Original assignee: Ultramed International, Inc.
Priority date: 2000-04-07
Filing date: 2001-04-05
Publication date: 2001-10-18
Also published as: AU2001251374A1

Abstract

Disclosed and claimed are methods and compositions for maintaining abstinence in a patient treated for opiate detoxification. Specifically, the invention provides two transdermal patches, each one administered during a distinct phase of recidivism that follows conventional detoxification, the first of which contains a side-effect blocking sedative/anti-hypertensive, a narcotic antagonist, a sedative, and octapeptide, and the latter contains the side-effect blocking sedative/anti-hypertensive and the narcotic antagonist.

Description

Title too long, PCT Rule 4.3. suggested new title follows: "MAINTAINING ABSTINENCE AFTER DETOXIFICATION FROM OPIATE ADDICTION"

CROSS-REFERENCE TO RELATED APPLICATION

5 Reference is made to U.S. provisional patent application Serial No.

60/195,693, filed April 7, 2000, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods of maintaining abstinence after 10 detoxification of a patient being treated for opiate addiction. Specifically, the invention first provides a method of administering a side-effect blocking anti- hypertensive, a narcotic antagonist, a sedative, and octapeptide in a transdermal patch that is administered to the patient after detoxification during the acute and chronic phases that follow detoxification. 15 Documents cited in this application relate to the state-of-the-art to which this invention pertains. The disclosures of each of these references are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Current methods of detoxifying opiate addicts are flawed. At the end of 20 traditional detoxification therapy, a considerable amount of opiate remains in pharmacodynamically significant concentration near the receptor sites in the brain of the addict, and as the opiate concentration at these receptors gradually diminishes, the patient feels continued discomfort, often returning to exogenous opiate use in an effort to relieve the symptoms of withdrawal. 25 While a variety of methods have been developed to combat the initial detoxification problem, the prior art has failed to address the severe problem of recidivism of opiate addicts. No consensus exists regarding long-term treatment of opiate addicts. At one time it was believed that large enough doses of oral methadone would enable addicts to return to a socially productive life because their drug supply 30 problems would be satisfied and methodone would block any ill-effects of injected opiate and alleviate the addict's cravings. For some individuals, methadone is a long term answer to their addiction, but for others, methadone merely adds another layer of addiction to their existing problem.

Others have attempted to remedy this problem by altering the initial detoxification method, such that the patient is unaware of the withdrawal they are experiencing. For example, Gooberman, U.S. Patent No. 6,004,962, describes a method for rapid opiate detoxification which includes first sedating the patient and administering an aggressive opiate antagonist, such as naloxone hydrochloride. After about 3-4 hours, the patient is fully detoxed and a maintenance dose of opiate antagonist can be administered, e.g., naltrexone administered orally or subcutaneously, optionally in a time-released antagonist mixture. The antagonist maintenance therapy continues to release a minimum therapeutic dose at least once every three days for at least one week following the procedure. Gooberman asserts that this maintenance therapy should eliminate the mood-altering effects of any opiate the patient takes and can help to maintain sobriety while the patient is counseled. Simon, U.S. Patent No. 5,783,583, describes another method of rapid detoxification from opiates. Simon describes a method in which the patient is rendered unconscious and the narcotic antagonist nalmefene is administered intravenously. This initiates a withdrawal reaction, lasting only a short time, but which the patient is not conscious of. After detoxification, the acute phase of withdrawal is complete. But like Gooberman, Simon does not address the recidivism of the patient after the acute phase of detoxification is complete.

Detoxification programs often fail because of the long term discomfort and cravings experienced by the patient during traditional detoxification. Those who finally succeed in detoxifying via traditional means tend to relapse at a rate higher than 60% when measured six months after detoxification. Thus, only about 4 of 10 patients will detoxify, with less than half remaining drug-free after six months. Clearly there is a need for a method of maintaining abstinence after detoxification in a patient treated for opiate addiction which has not heretofore been addressed by prior art methods.

OBJECT OF THE INVENTION

Therefore, it is an object of this invention to devise a method of maintaining abstinence after detoxification of a patient treated for opiate addiction. The method consists of administering to a patient in need of such treatment at least one and preferably two transdermal patches, the first being administered during the acute phase after detoxification and the second being administered during the chronic phase after detoxification. The first patch should consist of a side-effect blocking antihypertensive, such as clonidine, a narcotic antagonist, such as nalmafene, a sedative, such as an antihistamine, e.g., diphenhydramine, and octapeptide. The second patch consists of the side-effect blocking sedative/anti-hypertensive and the narcotic antagonist.

It is also an object of the invention to provide transdermal patches useful for maintaining abstinence during the acute and chronic phases that follow traditional detoxification. Preferably, a first patch is provided which consists of a side-effect blocking anti-hypertensive, a narcotic antagonist, a sedative, and octapeptide, and the first patch is used during the acute phase after detoxification. The second patch preferably contains the side-effect blocking sedative/anti-hypertensive and the narcotic antagonist, and is used during the chronic phase after detoxification. Each of these transdermal patches may consist of a single patch with separate compartments for each composition or they may consist of several individual patches for each composition, packaged in a single unit.

SUMMARY OF THE INVENTION It has now been found that after detoxification from opiates, there is an acute and chronic phase of relapse, and that each of these phases should be treated as separate and distinct conditions following traditional detoxification. Therefore, after the patient has been detoxified by any standard protocol, the patient is first treated for the acute phase, preferably using a transdermal patch that consists of a side effect blocking sedative/anti-hypertensive, a narcotic antagonist, a sedative, and octapeptide. This treatment continues for approximately 7-10 days after detoxification. After the acute phase has been treated, the patient is treated for chronic recidivism, preferably using a transdermal patch containing the side-effect blocking sedative/anti- hypertensive and narcotic antagonist. The second patch is preferably administered for up to six months following detoxification.

Therefore, the present invention provides a method for maintaining abstinence after detoxification of a patient treated for opiate addiction. Preferably, the method consists of administering to a patient in need of such treatment at least one and preferably two transdermal patches, the first administered during the acute phase after detoxification and the second administered during the chronic phase after detoxification. The first patch consists of a side-effect blocking sedative/anti- hypertensive, such as clonidine, a narcotic antagonist, such as nalmafene, a sedative, such as an antihistamine, and octapeptide. The second patch consists of the side- effect blocking sedative/anti-hypertensive and the narcotic antagonist.

The present invention also provides transdermal patches useful for maintaining abstinence during the acute and chronic phases that follow traditional detoxification. Preferably, a first patch is provided which consists of a side-effect blocking sedative/anti-hypertensive, a narcotic antagonist, a sedative, and octapeptide, and the first patch is used during the acute phase after detoxification. The second patch preferably contains the side-effect blocking sedative/anti-hypertensive and the narcotic antagonist, and is used during the chronic phase after detoxification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has now been found that the clinical phase following detoxification, which has been termed the post-detoxification syndrome, consists of two distinct phases: acute and chronic. These phases after detoxification are clinically separate conditions. In the acute phase after detoxification, the patient experiences the following:

(a) A negative response to the naloxone challenge test (see, The Physician's Desk Reference 2000, p. 976). The naloxone challenge test consists of injecting intravenously 0.2 mg of naloxone and observing the patient for signs of withdrawal, especially piloerection, yawning, and pupillary dilatation for 20 minutes. If none of these signs appear, the physician repeats the injection with 0.6 mg of naloxone, and again observes the patient for 20 minutes for signs of withdrawal. If none of these signs appear, then the naloxone challenge test is negative and the patient has been successfully detoxified. If any of these signs appear at either stage of the test, then the test is positive and the patient has not been detoxified and requires additional treatment.

(b) Between 1-2 times normal minute ventilation. This refers to the amount of air that a patient breathes in one minute; a typical healthy 70 kg patient would breathe approximately 4-6 liters of air per minute, and in the acute phase after detoxification, the patient breathes faster than normal, i.e., approximately 6-8 liters per minute.

(c) A leftward displaced C0₂ response curve having a normal slope. The CO₂ response curve is constructed by having the patient breathe in a closed ventilation circuit and measuring the ventilatory response to increasing levels of carbon dioxide. A normal person slowly but steadily increases his ventilatory rate in response to increasing levels of carbon dioxide. The slope of this line is normal. Deviation in slope and intercept are characteristic of several respiratory diseases and drug effects, like the presence of pure narcotic agonists and mixed narcotic agonist- antagonist. It has been discovered that post detoxification, there are two distinct phases in the recovery of the carbon dioxide response curve back to normal (see table below).

(d) A slightly increased Hoffman Index that is greater than 1.3, but trends down toward normal over the course of the acute phase. The Hoffman Index is a measure of the beat to beat variability of heart rate. This, in turn, is a measure of the activity of the sympathetic nervous system. Patients that have a high Hoffman Index have high sympathetic nervous system activity, i.e., high serum catecholamine levels. Under anesthesia during detoxification the index rises to 2.0. During the acute phase after detoxification, the index is approximately greater than 1.3.

In the chronic phase of recovery, the patient experiences a negative response to the naloxone challenge test, normal minute ventilation, a normal CO₂ response curve having a normal slope, and a normal Hoffman Index. These symptoms are summarized in Table 1, below, which also shows the comparative symptoms of the patient before and during detoxification, as well as those symptoms of the non-addict.

Table 1

Therefore, the present invention provides a method for maintaining abstinence after detoxification of a patient treated for opiate addiction. The patient may be addicted to any opiate, including heroin, morphine, and methadone. In a preferred embodiment, the method is used to treat patients addicted to heroin. The patient first undergoes detoxification (using the methods outlined in e.g., U.S. Patent No. 5,783,583, using naloxone rather than nalmafene, and C. Gevirtz, "Pre- Anesthesia Assessment of the Patient for Ultra-rapid Opiate Detoxification", Anesthesiology News, June 2000), and once the patient is treated for the initial detoxification, he or she is treated for the post detoxification syndrome. During the acute phase, the patient is administered a first transdermal patch consisting of four distinct compositions, in either a single patch having separate compartments for each composition or in a unit comprised of four distinct patches.

The first composition in the first patch consists of a side-effect blocking sedative/antihypertensive, such as clonidine or another adrenergic agent, which prevents or retards the release of plasma catecholamine levels. It is believed that the alpha-2 agonist agent prevents the arrythrnias which result from high levels of serum catecholamines. Failure to protect against these high levels of catecholamines has led to several patient deaths from both arrythrnias and from stress ulcers in the stomach which produces massive hemorrhage. Therefore, the administration of clonidine or other adrenergic agent, minimizes the continued elevation of catecholamine levels after detoxification, as manifested by a reduction in stress-induced gastrointestinal bleeding. The second composition in the first patch consists of a narcotic antagonist, such as nalmafene, naltrexone, or naloxone. In a preferred embodiment, the narcotic antagonist is nalmafene. The third composition in the first patch contains an antihistamine. Preferably, the sedative is Benadril^®. The sedative is used to cure insomnia, which usually accompanies the acute phase after detoxification. Finally, the fourth composition in the first patch is octapeptide, which cures diarrhea and prevents regurgitation. The second patch consists of the side-effect blocking sedative/antihistamine and the narcotic antagonist. Like the first patch, the second patch may contain separate compartments for each composition or it may be a single unit containing two distinct patches. The first patch is administered for seven to ten days following the initial detoxification, and the second patch is administered during the chronic phase, i.e., up to six months following detoxification.

When nalmafene and clonidine are used together, it has been discovered that overall effect of relapse prevention is greater than either drug alone.

Each of the transdermal patches are preferably adhered to the patient by holographic adhesive tape. Holographic tape is preferred because medical personnel can easily ascertain whether the patch has been tampered with; when the patient tries to remove the patch, it visibly alters the appearance of the holographic tape.

Octapeptide must be dispensed from the transdermal patch by iontophoresis. This process requires the use of a watch battery which is included with the patch or within the cluster of patches. Reference is made to U.S. Patent No. 5,647,844 for a complete description of iontophoresis.

Transdermal patches are described in the following U.S. Patents: 5,736,154, 4,906,463, 4,685,911, 4,917,676, 4,666,441, 5,635,204, 5,356,632, and 4,626,539. Preferably, the transdermal patches of the invention consist of separate compartments or several patches housed in a single unit in order to avoid mixing the different compositions. In addition, each of the compositions require a porous membrane at the outlet having a different pore size. In a preferred embodiment, each compartment has a different pore size so that one can ensure that each component is released from the patch at a different time in the course of the therapy and at a different rate. Existing commercial designs for the various patches used in the present invention will be used with altered reservoir fills. The time course of release should be fairly constant over the day, i.e., a slope near zero, once a therapeutic level is achieved. The concentration of each composition used in the patches of the invention are individually tailored for each patient, depending upon the patient's body weight, height, age, sex, obesity, body fat distribution, body temperature, and condition of the particular patient.

In a preferred embodiment, while the patient is treated during the acute and chronic phases after detoxification, the patient is also monitored by medical personnel during the entire period following detoxification. For example, during the first 48 hours following detoxification, medical personnel contact the patient several times and provide specific instructions to the patient to maximize the patient's comfort in the time immediately following detoxification. Within the two weeks that follow, medical personnel contact the patient several times per week, and in the months that follow, contact with medical personnel will gradually decrease to monthly contact in order to ensure continuing progress and recovery.

EXAMPLES

The invention will now be further described with reference to the following non-limiting examples.

Prior to acceptance into the clinical program, a detailed psychological examination is performed with emphasis on the details of the current and past patterns of drug abuse, the motivations for detoxification and maintenance of abstinence, the absence of suicidal or homicidal ideation, and the presence of a family support system. A detailed pre-anesthesia assessment is performed by a board certified anesthesiologist (see Gevirtz, infra), with an emphasis on the patients' cardiac and pulmonary history and looking for the end-organ effects of drug abuse. This represents an improvement over previously described detoxification methodologies, i.e., Gooberman, supra, because mortalities have resulted from the use of CRNAs in evaluating and treating these critical care patients. It is also beyond their scope of practice. An informed consent is obtained with an emphasis on the risks of the detoxification procedure, as well as those associated with the devices and drugs used in maintaining abstinence. The patient is given a copy to take home with him to review prior to acceptance into the program. The patient must agree to participate in an aftercare psychological program prior to beginning detoxification. Detoxification - The patient disrobes and is placed in a critical care hospital bed. A board certified anesthesiologist reviews the patient's chart and re-enforces the informed consent with the patient. Intravenous access is established in a peripheral vein with one liter of lactated ringers solution. All subsequent medications are administered through the intravenous tubing, using a stopcock to prevent needle sticks. A small amount of local anesthetic agent, such as 50 mg lidocaine, is administered intravenously. The patient is administered 2-3 mg of midozalam and 2 nig/kg propofol, together with 0.6 mg clonidine, for the purpose of anesthesia after the patient is connected to blood pressure, pulse, pulse oximeter, respiratory, EKG, skin temperature, and end-expiratory CO₂ monitoring. The anesthesia machine has undergone the FDA mandated check-out. (Defibrillator and all emergency drugs are immediately available.)

The anesthesiologist is present throughout the induction and administration of the narcotic antagonists. A propofol infusion is prepared and administered to the patient (50 ml vial of 10 mg per ml). Strict aseptic precautions are observed in preparation. The propofol is administered according to the Bispectral Edge Monitor. A level of 50-60 is achieved. The patient is ventilated, intubated, and placed, briefly, on the ventilator. Cricoid pressure is applied during the intubation. Vital signs are recorded every five minutes during induction of anesthesia and every 5 minutes thereafter for the remainder of the procedure. Mivacutium, 0.08 mg/kg is administered. This facilitates intubation. 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. Naltrexone, 150 mg, is administered via the orogastric tube. The patient is administered naloxone, 0.4 mg IV, and observed for signs of withdrawal, i.e., piloerection and increased blood pressure. An infusion of naloxone, 25 mg, is started over 30 minutes and then naloxone, 1 mg per hour, is administered for 24 hours. The acute phase abstinence patch is then applied to allow for blood levels to be achieved prior to awakening. After three hours, the stomach is again evacuated. Sandostatin, 100 μg, is administered subcutaneously to prevent diarrhea. An H-2 blocking drug, such as ranitidine, 50 mg, is administered to prevent gastrointestinal ulceration. At the end of the procedure, approximately 4 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) swallowing; (c) responds appropriately to verbal stimuli; and (d) sustained head lift of five seconds. The orogastric tube is removed with the endotracheal tube. A medical alert bracelet is applied to the patient. The patient is also given a wallet card which contains information, including the different drugs the patient has received, as well as emergency contact telephone numbers. The physician is present at the termination of the procedure and during extubation. Post-Detoxification Syndrome Therapy The patient is administered the first transdermal patch containing the following compositions in separate compartments within the patch: (1) clonidine, 2.1 mg for 10 days; (2) nalmafene, up to 20 mg; (3) Benadril^®, 10 g; and (4) octapeptide, 8000 μg. Each composition is contained within a reservoir of the patch defined by an impervious backing and a porous membrane facing the portion of the patch that contacts the patient's skin. The patch is designed so that each of the compositions are dispensed at the following rates: (1) clonidine, 0.3 mg in 24 hours; (2) nalmafene, 1 mg in 24 hours; (3) Benadril^®, 200 mg in 24 hours; and (4) octapeptide, 200 μg in 24 hours. The first patch is adhered to the patient with holographic tape for 7-10 days, during which time the patient is monitored for clinical manifestations of the acute phase of withdrawal, e.g., using the naloxone challenge test, minute ventilation, CO₂ response curve, and Hoffman Index, as well as to monitor the patient's continued use of the patch, and to provide specific instructions to the patient to maximize the patient's comfort.

The first patch is removed and the patient is then administered the second transdermal patch containing the following compositions in separate compartments within the patch: (1) clonidine, 1 mg; and (2) nalmafene, 8 mg.' Each composition is contained within a reservoir of the patch defined by an impervious backing and a porous membrane facing the portion of the patch that contacts the patient's skin. The patch is designed so that each of the compositions are dispensed at the following rates: (1) clonidine, 0.1 mg in 24 hours; and (2) nalmafene, 0.4 mg in 24 hours. The second patch is adhered to the patient with holographic tape for 2 weeks - 6 months, during which time the patient is monitored for clinical manifestations of the chronic phase of withdrawal, e.g., using the naloxone challenge test, minute ventilation, CO₂ response curve, and Hoffinan Index, as well as to monitor the patient's continued use of the patch, and to provide specific instructions to the patient to maximize the patient's comfort. The above description of the invention is intended to be illustrative and not limiting. Various changes or modifications in the embodiments described may occur to those skilled in the art. These can be made without departing from the spirit or scope of the invention.

REFERENCES

1. Kienbaum, P. et al., Anesthesiology, 88 : 1154-61 (1998).

2. Hoffman, W.E. et al., J. Clinical Anesthesia, 10: 372-76 (1998).

3. Gold, M.S. et al., Am. J. Psychiatry, 136: 100-02 (1979).

Claims

CLAIMS;

1. A transdermal patch useful for maintaining abstinence during an acute phase that follows detoxification of a patient treated for opiate addiction, said patch comprising, as distinct compositions: (i) a side-effect blocking sedative/anti- hypertensive; (ii) a narcotic antagonist; (iii) a sedative; and (iv) octapeptide.

2. The transdermal patch of claim 1 wherein said compositions are contained within said patch in separate compartments, each compartment comprising an impervious backing and a porous membrane defining a drug reservoir between said backing and said membrane, the patch being applied with said membrane in direct contact with the skin of the patient, each separate compartment comprising a membrane having a pore size suitable for administration of the composition contained therein.

3. A transdermal patch useful for maintaining abstinence during a chronic phase that follows detoxification of a patient treated for opiate addiction, said patch comprising, as distinct compositions: (i) a side-effect blocking sedative/antihypertensive; and (ii) a narcotic antagonist.

4. A method of maintaining abstinence after detoxification of a patient treated for opiate addiction, wherein detoxification is followed by a first, acute phase and a second, chronic phase, said method comprising: administering to said patient a first transdenmal patch comprising, as distinct compositions, (i) a side-effect blocking sedative/anti-hypertensive; (ii) a narcotic antagonist; (iii) a sedative; and (iv) octapeptide, said first patch being administered during said acute phase.

5. A method of maintaining abstinence after detoxification of a patient treated for opiate addiction, wherein detoxification is followed by a first, acute phase and a second, chronic phase, said method comprising:

(a) administering to said patient a first transdermal patch comprising, as distinct compositions, (i) a side-effect blocking sedative/anti-hypertensive; (ii) a narcotic antagonist; (iii) a sedative; and (iv) octapeptide, said first patch being administered during said acute phase; and (b) administering to said patient a second transdermal patch comprising, as distinct compositions, (i) a side-effect blocking sedative/anti-hypertensive; and (ii) a narcotic antagonist, said second patch being administered during said chronic phase.