WO1999063935A2 - Cure rapide de desintoxication aux opioïdes et traitement contre la rechute toxicomaniaque - Google Patents

Cure rapide de desintoxication aux opioïdes et traitement contre la rechute toxicomaniaque Download PDF

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WO1999063935A2
WO1999063935A2 PCT/US1999/012763 US9912763W WO9963935A2 WO 1999063935 A2 WO1999063935 A2 WO 1999063935A2 US 9912763 W US9912763 W US 9912763W WO 9963935 A2 WO9963935 A2 WO 9963935A2
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patient
antagonist
administering
therapy
sedating
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PCT/US1999/012763
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WO1999063935A3 (fr
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U.S. Detox, Inc.
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Priority to AU44259/99A priority Critical patent/AU4425999A/en
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Publication of WO1999063935A3 publication Critical patent/WO1999063935A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • 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.
  • naloxone naloxone hydrochloride
  • clonidine clonidine hydrochloride
  • 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.
  • 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.
  • 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.
  • 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).
  • ondansetron a selective 5-HT3 receptor antagonist, generally used to prevent nausea and vomiting associated with cancer chemotherapy.
  • naltrexone 50 mgs
  • 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").
  • ROD rapid opiate detoxification
  • Legarda belongs to the CITA group, which has been detoxifying heroin patients in Spain, Israel and Mexico under general anesthesia.
  • Legarda and Gossop used intravenous midazolam (0.5-0.7 mgs/kg initially, then as a constant infusion) for sedation.
  • 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.
  • guanfacine like clonidine, a centrally acting agent with alpha-2 agonist properties
  • Oral doses of loperamide (4 mgs) and ondansetron (8 mgs) were given, to avoid diarrhea and vomiting during the detoxification procedure.
  • the subjects' opiate withdrawal signs primarily were piloerection, sneezing and motor agitation.
  • benzodiazepines such as midazalom
  • Flumazenil competitively inhibits the activities at the benzodiazepine recognition site on the brain's receptor complex.
  • benzodiazepines such as Zanax, Halcion, or Valium
  • the use of flumazenil to reverse the effects of benzodiazepine anesthesia can cause seizures.
  • 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.
  • naloxone hydrochloride l-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.
  • 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.
  • the present invention provides for rapid detoxification of opioid addicts, including those who are dually-addicted to opiates and benzodiazepines.
  • 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.
  • 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.
  • 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.
  • vomiting is a frequent side effect.
  • a tube can be placed in the airway with an inflated cuff.
  • 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.
  • the patient can be revived nearly immediately. This is not the case with conventional ROD procedures.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions can also include time-release agents, erosion rate modifiers, antimicrobial agents and surfactants.
  • 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.
  • 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 CO 2 monitoring. (Defibrillator and all emergency drugs are immediately available).
  • 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.
  • the propofol drip is commenced 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.
  • nalmefene 2 mg IV 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).
  • 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 ex ubated 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.
  • the patient 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-proced
  • 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
  • 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 C0 2 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.
  • 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.
  • Naltrexone (Re Via) 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.
  • 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.
  • 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.
  • a GABA B 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 GABA B agonist there has been shown a marked decrease in nausea and vomiting associated with the opiate withdrawal.
  • BACLOFEN Lioresal
  • a GABA B 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 GAB A agonists can be administered virtually at any time before, during or after the inventive procedure.
  • Naltrexone 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.
  • DNTX subcutaneous depot NTX
  • 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.
  • 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.
  • 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 IB for the 1000 mg pellets. There appeared to be no consistent systemic levels.
  • 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.
  • NTX pellet 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.
  • 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 present invention presents the first extended clinical experience with any DNTX preparation.
  • 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.

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Abstract

Cette invention est une cure rapide de désintoxication aux opioïdes consistant à calmer le patient au moyen d'un agent anesthésiant à courte période de récupération complète. On administre au patient un antagoniste d'opioïde pendant que le sédatif fait effet. Le patient peut reprendre un régime ambulatoire dans les huit heures suivant le début du traitement. Cette cure de désintoxication comporte également une administration d'un antidiarrhéique tel que l'octréotide à l'état acétate pour limiter cet effet délétère de la cure de désintoxication. L'invention concerne également un traitement permettant de réduire les symptômes liés au sevrage aux opiacés et consistant en une administration d'un antagoniste du GABAB.
PCT/US1999/012763 1998-06-09 1999-06-08 Cure rapide de desintoxication aux opioïdes et traitement contre la rechute toxicomaniaque WO1999063935A2 (fr)

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AU44259/99A AU4425999A (en) 1998-06-09 1999-06-08 Rapid opioid detoxification therapy and anti-readdiction therapy

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US09/094,152 1998-06-09

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075341A (en) * 1989-12-01 1991-12-24 The Mclean Hospital Corporation Treatment for cocaine abuse
US5173282A (en) * 1991-10-04 1992-12-22 Mobil Oil Corp. Synthesis of crystalline mordenite-type material
US5272149A (en) * 1992-05-05 1993-12-21 Stalling Reginald W Symptom controlled receptor substitution for addiction withdrawl

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075341A (en) * 1989-12-01 1991-12-24 The Mclean Hospital Corporation Treatment for cocaine abuse
US5173282A (en) * 1991-10-04 1992-12-22 Mobil Oil Corp. Synthesis of crystalline mordenite-type material
US5272149A (en) * 1992-05-05 1993-12-21 Stalling Reginald W Symptom controlled receptor substitution for addiction withdrawl

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WO1999063935A3 (fr) 2000-04-13

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