WO1994016755A1

WO1994016755A1 - Intrapulmonary delivery of narcotics

Info

Publication number: WO1994016755A1
Application number: PCT/US1994/000999
Authority: WO
Inventors: Reid M. Rubsamen
Original assignee: Miris Medical Corporation
Priority date: 1993-01-29
Filing date: 1994-01-27
Publication date: 1994-08-04
Also published as: AU6097694A

Abstract

Pain management is provided by the intrapulmonary delivery of a pharmaceutically active pain relief formulation. The formulation is automatically released from a handheld, self-contained, portable device (1) comprised of a means (7) for automatically releasing a measured amount of drug into the inspiratory flow path of a patient in response to information obtained from a means (22) for analyzing the inspiratory flow of a patient. Patient compliance and accuracy in dosing are obtained by providing for automatic release in response to a measure inhalation profile. Abuse of narcotic formulations is avoided by providing a tamper resistant device which includes a variety of security features including a preprogrammed microprocessor (22) designed to avoid overdosing.

Description

INTRAPULMONARY DELIVERY OF NARCOTICS

Field of the Invention

This invention relates generally to methods of pain management by the administration of narcotics. More specifically, this invention relates to the intrapulmonary delivery of narcotics from a hand-held, self-contained device capable of automatically releasing a controlled amount of narcotics to a patient at an optimal point in the respiratory cycle of the patient.

Background of the Invention

Narcotic therapy forms the mainstay of pain management. These drugs can be administered in many forms to patients with postsurgical and other forms of acute and chronic pain. Morphine, one of the oldest narcotics, is available for administration in tablet or in injectable form. Fentanyl, a synthetic narcotic, was first synthesized in 1960 by Paul Janssen and found to be 150 times more potent than morphine [Theodore Stanley, "The History and Development of the Fentanyl Series," Journal of Pain and Symptom Management (1992) 7 : 3 (suppl . ) , S3 -S7] . Fentanyl and its relatives Sufentanil and Alfentanil are available for delivery by injection. In addition, fentanyl is available for administration by a transdermal delivery system in the form of a skin patch [Duragesic™ (fentanyl transdermal system) package insert, Janssen Pharmaceutica, Piscataway, NJ 08855, Jan-Jun 1991] .

A feature of the synthetic narcotic fentanyl is that is has a more rapid time to onset and a shorter duration of action than morphine. This makes fentanyl a useful drug for the management of acute pain. Currently, fentanyl is typically given by intravenous injection for acute pain management. Although fentanyl can be given by a transdermal patch, transdermal delivery of fentanyl is designed for long-term administration of the drug and does not lend itself to achieving a peak level rapidly for a short-term effect.

An alternative to delivery by injection for narcotics is delivery by inhalation. Morphine

[J. Chrusbasik et al. , "Absorption and Bioavailability of Nebulized Morphine, " Br. J. Anaesth . (1988) 61 , 228 -30] , fentanyl [M.H. Worsley et al., "Inhaled Fentanyl as a Method of Analgesia," Anaesthesia (1990) 45, 449 -51] , and sufentanil [A.B. Jaffe et al., "Rats Self-administer

Sufentanil in Aerosol Form, " Psychopharmacology, (1989) 99 , 289 -93] have been shown to be deliverable as aerosols into the lung. The pilot study described by Worsley suggested that "inhaled fentanyl is an effective, safe and convenient method of analgesia which merits further investigation. "

Inhalation of a potent synthetic narcotic aerosol provides a mechanism for the non-invasive delivery of rapid-acting boluses of narcotic. The on- demand administration of boluses of narcotic coupled with a controlled baseline intravenous infusion of narcotic is termed "patient-controlled analgesia" (PCA) and has been found to be a very effective means of postoperative pain management . Demand analgesia was first introduced in 1968 by Schetzer who showed it to be an effective mechanism for treating postoperative patients [Maureen Smythe, "Patient-Controlled Analgesia: A Review, " Pharmacotherapy (1992) , 12 :2, 132 -43] . Prior to the availability of patient-controlled analgesia, the paradigm for postoperative pain management consisted of intermittent intramuscular injections of narcotic. The cycle of the patient felling pain, calling the nurse who then must locate and bring the drug to the bedside for administration results in suboptimal postoperative pain management [Philip Shade, "Patient-controlled Analgesia: Can Client Education Improve Outcomes?," Journal of Advanced Nursing (1992) 17, 408 -13] . Postoperative pain management by intermittent narcotic administration has been shown to be a largely ineffective method of pain management for many of the patients undergoing the more than 21 million surgical procedures in the United States each year [John Camp, "Patient-Controlled Analgesia, " AFP (1991) , 2145-2150] . Even if every patient reliably received a constant dose of narcotic postoperatively, studies of therapeutic narcotic pharmacokinetic data have shown that patient variability makes such an approach fundamentally unsound and potentially dangerous [ .E. Mather, "Pharmacokinetics and Patient-Controlled Analgesia," Acta Anaesthesiologica Belgica (1992) 43 : 1 , 5 -20] .

The first commercial device for automatically providing intravenous patient-controlled analgesia was developed in Wales in the mid-1970s. This device, the Cardiff Palliator (Graesby Medical Limited, United Kingdom) is the predecessor of numerous currently available computer-controlled patient-controlled analgesia intravenous pumps [Elizabeth Ryder, "All about Patient-Controlled Analgesia, " Journal of Intravenous Nursing (1991) 14 , 372 - 81] . Studies using these computer controlled intravenous narcotic infusion pumps have shown that small doses of narcotics given on demand by the patient provided superior pain relief when compared with intermittent intramuscular administration of these drugs [Morton Rosenburg, "Patient-Controlled Analgesia, " J. Oral Maxillofac Surg (1992) 50, 386- 89] .

These computer-controlled pumps typically allowed for the programming of four different parameters: 1) .basal intravenous narcotic infusion rate; 2) the bolus of narcotic to be delivered on each patient demand; 3) the maximum hourly total dose of narcotic to be allowed; and 4) the lockout period between doses. Typical programming for postoperative pain management with intravenous fentanyl might be a basal infusion rate of 20 μg/hr, a bolus demand dose of 20 μg, a maximum hourly does of 180 μg, and a lockout period between doses of 5 minutes. In a study of 30 patients treated for postoperative pain with intravenous fentanyl patient- controlled analgesia, the minimum effective concentration (MEC) of fentanyl in the blood required to achieve pain relief in the group of patients studies was found to range from 0.23 to 1.18 ng/ml. Clinically significant respiratory depression was not seen in this study consistent with published data indicating that a fentanyl concentration of 2 ng/ml in the blood is typically required to depress the respiratory rate [Geoffrey Gourlay et al. , "Fentanyl Blood Concentration — Analgesic Response Relationship in the treatment of Postoperative Pain," Anesth Analg (1988) 67, 329 -37] .

The administration of narcotic for pain management is potentially dangerous because overdoses of narcotics will cause complications such as respiratory depression. The patient's respiratory rate is decreased by the Administration of narcotics. This decrease in respiratory rate may not be associated with a change in respiratory tidal volume [Miller, Anesthesia (2nd ed) , Churchill Livingston, I, 762] . The four programmable parameters available on computer-controlled intravenous patient-controlled analgesia infusion pumps must be selected so as to minimize the likelihood of narcotic overdose. The preferred technique is to set the basal infusion rate at a relatively low rate and increase this rate based on how many times the patient presses the bolus demand button to self-administer supplemental drug. As long as the patient himself or herself is the only one to push the demand button, respiratory depression is unlikely. However, there have been documented cases of the patient's family and friends pressing the narcotic demand button, for instance while the patient is sleeping [Robert Rapp et al., "Patient- controlled Analgesia: A Review of the Effectiveness of Therapy and an Evaluation of Currently Available Devices," DICP, The Annals of Pharmacotherapy (1989) 23 , 899 -9040] .

It is a problem with patient-controlled analgesia that it must currently be performed using an intravenous infusion pump. This requires that an indwelling catheter be placed in the patient's vein and that the patient transport a relatively bulky system with himself at all times to receive a baseline infusion of intravenous narcotic and allow for intermittent on-demand self-bolusing of additional narcotic in order to match the patient's changing need for drug. A portable PCA device incorporating a wristwatch-like interface has been described [D.J. Rowbotham, "A Disposable Device for Patient-Controlled Analgesia with Fentanyl," Anaesthesia (1989) 44 , 922 -24] . This system incorporated some of the features of computer-controlled programmable PCA infusion pumps such as basal infusion rate and the amount of each bolus. However, this system, which involved the use of an intravenous catheter as seen in larger infusion pumps, incorporated no provision to record accurately the actual dose of Fentanyl administered to the patient over time. Although fentanyl can be administered by transdermal patch, this method has been found to be suboptimal for postoperative main management [K.A. Lehmann et al., "Transdermal Fentanyl for the Treatment of Pain after Major Urological Operations, Eur. J. Clin Pharmacol (1991) 21 : 17-21] . Lehmann found that the low dose of narcotic delivered by transdermal fentanyl was inadequate to provide pain relief to many of his patients and that boosting the baseline infusion rate of the patch would put some patients at risk for having significant respiratory depression. In addition, he points out that if such a complication were to appear in conjunction with the delivery of narcotic by transdermal patch, the infusion could not be quickly stopped because the "cutaneous fentanyl depot" created by the transdermal patch would cause narcotic infusion to continue even after removal of the patch.

Delivery of fentanyl by aerosol used in conjunction with a non-invasively delivered long-acting preparation of narcotic such as slow-release oral morphine or a fentanyl transdermal patch provides a means for non-invasive administration of a basal rate of narcotic and rapid-acting boluses of narcotic to an ambulatory patient. It is a problem with the aerosol delivery of fentanyl previously described that inefficient, bulky nebulizers must be used for the administration of the drug. In addition, these nebulizers work by administering from an open reservoir of the drug in aqueous solution allowing the vapor to be generally distributed and creating the potential for overdosing due to the lack of reproducible aerosol delivery. In addition, abuse through theft of the aqueous-phase fentanyl and subsequent unauthorized repackaging of this controlled substance in an aqueous injectable form are possible.

Because most surgery today is being done on ambulatory patients and because these patients are often rapidly discharged from the hospital and because patient- controlled analgesia has been identified as the preferred method of postoperative pain management, it is desirable to have a safe and effective method for non-invasive, ambulatory patient-controlled analgesia.

Summary of the Invention

A method of pain control is provided by the intrapulmonary delivery of a pharmaceutically active pain relief formulation. The formulation is automatically released from a hand-held, self-contained, portable device comprised of a means for automatically releasing a measured amount of drug into the inspiratory flow path of a patient in response to information obtained from a means for analyzing the inspiratory flow of a patient. Reproducible dosing is obtained by providing for automatic release in response to a measured inhalation profile. Abuse of narcotic formulations is avoided by providing a tamper-resistant device which includes a variety of security features including a pre-programmed microprocessor designed to avoid overdosing.

It is an object of this invention to describe a method of aerosolized delivery of potent narcotic in a safe and effective manner.

An advantage of the present invention is that it can be used for ambulatory patients.

A feature of the invention is that aerosolized potent narcotics can be used in conjunction with a non- invasively delivered baseline infusion rate of narcotic to provide a complete method for patient-controlled analgesia for ambulatory patients. Another feature of this invention is that formulations of narcotics such as fentanyl and a highly volatile propellant provide for a fundamentally tamper- resistant package making it difficult for the contained fentanyl to be illicitly repackaged in an injectable form.

It is another object of the invention to provide a metered-dose inhaler canister comprising a formulation of narcotic such as fentanyl packaged in a manner such that it can only be used in conjunction with a particular apparatus described.

Another advantage is that the device can be programmed to provide a minimum required time interval between doses. Another advantage of the invention is that the device can be programmed so as to control the maximum amount of narcotic delivered within a period of time.

Yet another advantage is to provide a device which can be simultaneously programmed to control the maximum amount of narcotic drug delivered within a given period of time and provide for a minimum required time interval between the delivery of doses.

A feature of the invention is that it can monitor the amount of aerosolized narcotic delivered to a patient and record amounts and times of delivery for review by a treating physician.

Another advantage of the invention is that the apparatus can monitor respiratory rate to ensure that respiratory depression has not supervened prior to further administration of narcotic.

Another object of this invention is to provide an apparatus which can analyze the breathing pattern of the patient not only to determine the respiratory rate prior to delivery but also to determine the inspiratory flow profile characteristics so as to determine the optimal point in the inspiratory cycle for delivery of aerosolized potent narcotic.

Yet another object of this invention is to further provide aerosolized naloxone which may be administered to counteract the effects of administered potent narcotic in the event of the development of complications such as respiratory depression due to overdose of the narcotic.

Another advantage is that the method described provides for reproducible delivery of narcotics such as fentanyl wherein the reproducibility is a critical part of safety causing each dose of narcotic to have the same clinical effect.

Another object is to provide an electronic lock-and-key system which can ensure that only the intended authorized patient can inhale aerosolized narcotic from the described apparatus making unauthorized users unable to inhale drug from the system.

These and other objects, advantages and features of the present invention will become apparent to those skilled in the art upon reading this disclosure in combination with drawings wherein like numerals refer to like components throughout.

Brief Description of the Drawings

Figure 1 is a cross-sectional view of a drug delivery device;

Figure 2 is a cross-sectional view of a more preferred embodiment of a drug delivery device; Figure 3 is a perspective view showing a pressurized canister with the canister cover components disconnected; and

Figure 4 is a perspective view of another embodiment of the cover components connected and the canister held therein. Detailed Description of the Preferred Embodiments

Before the present method of pain management and devices and formulations used in connection with such are described, it is to be understood that this invention is not limited to the particular methodology, devices and formulations described, as such methods, devices and formulations may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a formulation" includes mixtures of different formulations, reference to "an antagonist" includes a plurality of such compounds, and reference to "the method of treatment" includes reference to equivalent steps and methods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe and disclose specific information for which the reference was cited in connection with.

The term "dosing event" shall be interpreted to mean the administration of analgesic drug to a patient in need thereof by the intrapulmonary route of administration which event may encompass one or more releases of analgesic drug formulation from an analgesic drug disper ing device over a period of time of 15 minutes or less, preferably 10 minutes or less, and more preferably 5 minutes or less, during which period multiple inhalations are made by the patient and multiple doses of analgesic drug are released and inhaled. A dosing event shall involve the administration of analgesic drug to the patient in an amount of about 1 μg to about 100 mg in a single dosing event which may involve the release of from about 10 μg to about 1000 mg of analgesic drug from the device.

The term "monitoring event" shall be interpreted to mean an event taking place prior to a "dosing event" whereby the inspiratory flow of the patient's inhalation is measured in order to determine an optimal inspiratory flow rate and cumulative volume at which to allow the release of a valve so that analgesic drug can be delivered to the patient. It is preferable to carry out a "monitoring event" prior to each "dosing event" so as to optimize the ability to repeatedly deliver the same amount of analgesic drug to the patient at each dosing event.

The term "inspiratory flow" shall be interpreted to mean a value of airflow calculated based on the speed of the air passing a given point along with the volume of the air passing that point with the volume calculation being based on integration of the flow rate data and assuming atmospheric pressure and temperature in the range of about 18°C to about 30°C. The term "inspiratory flow profile" shall be interpreted to mean data calculated in one or more monitoring events measuring inspiratory flow rate and cumulative volume which profile can be used to determine a point within a patient's respiratory cycle which is optimal for the release of analgesic drug to the patient. It is emphasized that the optimal point within the respiratory cycle for the release of analgesic drug is not calculated based on a point within the cycle likely to result in the maximum delivery of analgesic drug but rather the point in the cycle most likely to result in the delivery of the same amount of analgesic drug to the patient at each release of analgesic drug from the device.

The term "analgesic drug" shall be interpreted to mean a drug for treating symptoms of pain. Analgesic drugs may include one of: narcotics, nonsteroidal antiinflammatory drugs and mixed agonist-antagonistic drugs such as butorphanol. Examples of useful narcotics drugs are described and disclosed within the Physicians Desk Reference and the Drug Evaluations Annual 1993, published by the American Medical Association, both of which are incorporated herein by reference. The invention encompasses the free acids, free bases, salts, hydrates in various formulations of analgesic drugs useful for pain control.

General Methodology

A non-invasive means of pain management is provided in a manner which makes it possible to maintain tight control over the amount of drug administered to a patient suffering with pain. An essential feature of the invention is the intrapulmonary delivery of analgesic drug to the patient in a controlled and repeatable manner. The device of the invention provides a number of features which make it possible to achieve the controlled and repeatable dosing procedure required for pain management. Specifically, the device is not directly actuated by the patient in the sense that no button is pushed nor valve released by the patient applying physical pressure. On the contrary, the device of the invention provides that the valve releasing analgesic drug is opened automatically upon receipt of a signal from a microprocessor programmed to send a signal when data is received from a monitoring device such as an airflow rate monitoring device. A patient using the device withdraws air from a mouthpiece and the inspiratory rate, and calculated inspiratory volume of the patient is measured one or more times in a monitoring event which determines an optimal point in an inhalation cycle for the release of a dose of analgesic drug.

Inspiratory flow is measured and recorded in one or more monitoring events for a given patient in order to develop an inspiratory flow profile for the patient. The recorded information is analyzed by the microprocessor in order to deduce a preferred point within the patient's inspiratory cycle for the release of analgesic drug with the preferred point being calculated based on the most likely point to result in a reproducible delivery event. The flow rate monitoring device continually sends information to the microprocessor, and when the microprocessor determines that the optimal point in the respiratory cycle is reached, the microprocessor actuates the opening of the valve allowing release of analgesic drug. Accordingly, drug is always delivered at a pre- programmed place in the inspiratory flow profile of the particular patient which is selected specifically to maximize reproducibility of drug delivery and peripheral deposition of the drug. It is pointed out that the device of the present invention can be used to, and actually does, improve the efficiency of drug delivery. However, this is not the critical feature. The critical feature is the reproducibility of the release of a tightly controlled amount of drug at a particular point in the respiratory cycle so as to assure the delivery of a controlled and repeatable amount of drug to the lungs of each individual patient.

The combination of automatic control of the valve release, combined with frequent monitoring events in order to calculate the optimal flow rate and time for the release of analgesic drug, combine to provide a repeatable means of delivering analgesic drug to a patient. Because the valve is released automatically and not manually, it can be predictably and repeatedly opened for the same amount of time each time or for the preprogrammed measured amount of time which is desired at that particular dosing event. Because dosing events are preferably preceded by monitoring events, the amount of analgesic drug released and/or the point in the inspiratory cycle of the release can be readjusted based on the particular condition of the patient. For example, if the patient is suffering from a condition which allows for a certain degree of pulmonary insufficiency, such will be taken into account in the monitoring event by the microprocessor which will readjust the amount and/or point of release of the analgesic drug in a manner calculated to provide for the administration of the same amount of analgesic drug to the patient at each dosing event. it has been found that the ability to tightly control the amount of a volatile propellant formulation of drug delivered via the intrapulmonary route can be improved by delivering smaller doses of the propellant/drug formulation with each release of the valve and with each dosing event. Repeatability, in terms of the amount of analgesic drug delivered to a patient, is improved when the analgesic drug is delivered during a smooth, normal inhalation by the patient. To a certain extent, the ability to provide for a smooth inhalation is enhanced when smaller amounts of analgesic drug are released as compared with larger amounts of analgesic drug. Accordingly, an important aspect of the invention is to deliver aerosolized analgesic drug to a patient in a series of interrupted bursts while the patient continues a single inhaled breath, with each burst being delivered while the patient maintains optimal inspiratory flow.

Short bursts of the release of analgesic drug can be obtained as two or more bursts but are preferably three or four bursts. The amount of time the valve is opened is generally in the range of about 0.05 seconds to l second but is more preferably 0.1 seconds to 0.25 seconds. When the analgesic drug is being released in a series of short bursts, it is preferable for the valve to be open a substantially shorter period of time than the valve is closed. For example, the valve might be opened for approximately 0.1 seconds and closed for approximately 0.5 seconds, followed by another opening of 0.1 seconds and another closing of 0.5 seconds, with this pattern being repeated a plurality of times.

Repeatability and dosing can be improved by providing for four bursts, wherein each burst allows for the valve to be opened four times, separated by three closings, wherein the amount of closed time is two to eight times longer than the amount of open time for each on/off event. Particularly preferred repeatability can be obtained by allowing for four bursts, wherein the valve is opened for approximately 0.015 seconds, followed by a closing for approximately 0.1 second, which pattern is repeated for four openings, separated by three closings.

The amount of analgesic drug delivered to the patient will vary greatly depending on the particular drug being delivered. In accordance with the present invention it is possible to deliver a wide range of different narcotic drugs with the most preferred drug being sufentanil which is generally administered to a patient in an amount in the range of about 10 μg - 100 μg. It is pointed out that sufentanil is approximately ten times more potent than fentanyl so that fentanyl is generally delivered to a patient in an amount of about 100 μg - 1000 μg. These doses are based on the assumption that when interpulmonary delivery methodology is used the efficiency of the delivery is approximately 10% and adjustments in the amount released must be made in order to take into account the efficiency of the device. The differential between the amount of analgesic drug actually released from the device and the amount of analgesic drug actually delivered to the patient varies due to a number of factors. In general, the present device is approximately 20% efficient, however, the efficiency can be as low as 10% and as high as 50% meaning that as little as 10% of the released analgesic drug may actually reach the circulatory system of the patient and as much as 50% might be delivered. The efficiency of the delivery will vary somewhat from patient to patient and must be taken into account when programming the device for the release of analgesic drug. In general, a conventional metered dose inhaling device is about 10% efficient. When administering analgesic drug using the inhalation device of the present invention, the entire dosing event can involve the administration of anywhere from 1 μg to 100 mg, but more preferably involves the administration of approximately 10 μg to 10 mg. The large variation in the amounts which might be delivered are due to the fact that different drugs have greatly different potencies and may be delivered from devices which vary greatly in terms of the efficiency of drug delivered. The entire dosing event may involve several inhalations by the patient with each of the inhalations being provided with multiple bursts of analgesic drug from the device. For example, the device can be programmed so as to release enough analgesic drug so that approximately 1 mg of analgesic drug is delivered to the patient per inhalation or 0.33 mg of analgesic drug per burst with three bursts being delivered per inhalation. If ten mg are to be delivered, the ten mg are delivered by releasing 33 bursts in ten different inhalations. Such a dosing event should take about 1-2 minutes to deliver 10 mg of analgesic drug. Since only small amounts are delivered with each burst and with each inhalation, even a complete failure to deliver analgesic drug with a given inhalation or burst is not of great significance and will not seriously disturb the reproducibility of the dosing event. Further, since relatively small amounts are delivered with each inhalation and/or burst, the patient can safely administer a few additional milligrams of analgesic drug without fear of overdosing. in addition to drug potency and delivery efficiency, analgesic drug sensitivity must be taken into consideration. The present invention makes it possible to vary dosing over time if analgesic sensitivity changes and/or if user compliance and/or lung efficiency changes over time.

Based on the above, it will be understood that the dosing or amount of analgesic drug actually released from the device can be changed based on the most immediately prior monitoring event wherein the inspiratory flow of a patient's inhalation is measured. Variations in doses are calculated by monitoring the effect of respiratory rate in response to known amounts of analgesic drug released from the device. If the response in decreasing the patient's respiratory rate is greater than with previous readings, then the dosage is decreased or the minimum dosing interval is increased. If the response in decreasing respiratory rate is less than with previous readings, then the dosing amount is increased or the minimum dosing interval is decreased. The increases and decreases are gradual and are preferably based on averages (of 10 or more readings of respiratory rates after 10 or more dosing events) and not a single dosing event and monitoring event with respect to respiratory rates. The present invention can record dosing events and respiratory rates over time, calculate averages and deduce preferred changes in administration of analgesic drug.

One of the important features and advantages of the present invention is that the microprocessor can be programmed to take two different criteria into consideration with respect to dosing times. Specifically, the microprocessor can be programmed so as to include a minimum time interval between doses i.e. after a given delivery another dose cannot be delivered until a given period of time has passed. Secondly, the timing of the device can be programmed so that it is not possible to exceed the administration of a set maximum amount of drug within a given time. For example, the device could be programmed to prevent dispersing more than 200 micrograms of a narcotic within one hour. More importantly, the device can be programmed to take both criteria into consideration. Thus, the device can be programmed to include a minimum time interval between doses and a maximum amount of drug to be released within a given time period. For example, the microprocessor could be programmed to allow the release of a maximum of 200 micrograms of a narcotic during an hour which could only be released in amounts of 25 micrograms with each release being separated by a minimum of five minutes. The dosing program can be designed with some flexibility. For example, if the patient normally requires 25 mg per day of analgesic drug, the microprocessor of the inhalation device can be programmed to prevent further release of the valve after 35 mg have been administered within a given day. Setting a slightly higher limit would allow for the patient to administer additional analgesic drug, if needed, due to a higher degree of pain and/or account for misdelivery of analgesic drug such as due to coughing or sneezing during an attempted delivery.

The ability to prevent overdosing is a characteristic of the device due to the ability of the device to monitor the amount of analgesic drug released and calculate the approximate amount of analgesic drug delivered to the patient based on monitoring given events such as the respiratory rate. The ability of the present device to prevent overdosing is not merely a monitoring system which prevents further manual actuation of a button. As indicated above, the device used in connection with the present invention is not manually actuated, but is fired in response to an electrical signal received from a microprocessor (which received data from a monitoring device such as a device which monitors inspiratory flow) and allows the actuation of the device upon achieving an optimal point in a inspiratory cycle. When using the present invention, each release of the valve is a release which will administer drug to the patient in that the valve is released in response to patient inhalation. More specifically, the device does not allow for the release of analgesic drug merely by the manual actuation of a button to fire a burst of analgesic drug into the air or a container. The microprocessor of applicant's invention will also include a timing device. The timing device can be electrically connected with visual display signals as well as audio alarm signals. Using the timing device, the microprocessor can be programmed so as to allow for a visual or audio signal to be sent when the patient would be normally expected to administer analgesic drug. In addition to indicating the time of administration (preferably by audio signal) , the device can indicate the amount of analgesic drug which should be administered by providing a visual display. For example, the audio alarm could sound alerting the patient that analgesic drug should be administered. At the same time, the visual display could indicate "50 μg" as the amount of analgesic drug to be administered. At this point, a monitoring event could take place. After completion of the monitoring event, administration would proceed and the visual display would continually indicate the remaining amount of analgesic drug which should be administered. After the predetermined dose of 50 μg had been administered, the visual display would indicate that the dosing event had ended. If the patient did not complete the dosing event by administering the stated amount of analgesic drug, the patient would be reminded of such by the initiation of another audio signal, followed by a visual display instructing the patient to continue administration.

Additional information regarding dosing with analgesic drug via injection can be found within Anesthesa, (most recent edition) edited by Miller,

Churchill and Livingston and Harrison's — Principles of Internal Medicine (most recent edition) published by McGraw Hill Book Company, New York, incorporated herein by reference to disclose conventional information regarding dosing analgesic drug via injection. Supplemental Treatment Methodology

Patients suffering from pain may be treated solely with analgesic drug as indicated above, i.e. by intrapulmonary delivery. However, it is possible to treat such patients with a combination of analgesic drug(s) provided by other means of administration. More specifically, a patient can be provided with a basal level of analgesic drug by a means such as transdermal administration and/or oral administration. This basal level of drug will be sufficient to control the pain of the patient during normal circumstances. However, when the pain becomes more intense, the patient can quickly obtain relief by the intrapulmonary administration of an analgesic drug such as sufentanil using the device and methodology of the present invention. The intrapulmonary delivery of analgesic drug provides a pulsalite rate increase over the normal basal rate level maintained by the oral or transdermal administration. The use of the intrapulmonary administration of analgesic drug via the present invention is particularly desirable in that the effects of the drug are felt almost immediately. Such an immediate effect cannot be obtained using oral and/or transdermal administration means.

Fentanyl is available for administration by a transdermal delivery system in the form of a skin patch [Duragesic™ (fentanyl transdermal system) package insert, Janssen Pharmaceutica, Piscataway, NJ 08855, Jan-Jun 1991] .

In addition to administering narcotics by transdermal administration it is possible to administer the drugs by other means such as by injection and/or orally. In accordance with the present invention a preferred supplemental means of administration is oral in that oral administration can be carried out on an out- patient basis. Thus, the method of the invention may be carried out by administering a long acting orally effective narcotic drug. The oral drug is preferably given in amount so as to maintain a relatively low level of narcotic within the circulatory system which is sufficient to control pain during periods when the pain is less severe. However, this low level of drug to blood ratio must be raised in order to control more severe pain and such can be accomplished by the interpulmonary administration of narcotic using the present invention. Based on the above, it will be understood by those skilled in the art that a plurality of different treatments and means of administration can be used to treat a single patient. For example, a patient can be simultaneously treated with analgesic drug by injection, analgesic drug via intrapulmonary administration in accordance with the present invention, and drugs, which are orally administered. Should such prove to be ineffective for whatever reason, such as breathing difficulties (not related to the administration of the analgesic drug) , such could be supplemented by administration via injection.

Treating Overdoses with Narcotic Antagonist

The methodologies of the present invention can be carried out using any type of analgesic drug, although they are preferably carried out using potent narcotic such as fentanyl and morphine. The biochemical mechanism of action of such narcotics is known. Further, it is known that the narcotic effect can be blocked by the administration of a narcotic antagonist such as naloxone.

Delivery Device

Before referring to the specific embodiments of the delivery device shown in Figures 1 and 2, an explanation will be provided regarding a general mechanism which can be used in connection with the method of intrapulmonary administration of narcotics. Such a device is a hand-held, portable device which is comprised of (a) a means for analyzing the inspiratory flow of a patient and (b) a means for automatically releasing a measured amount of a narcotic into the inspiratory flow path of a patient, e.g. an automatic valve actuation means. In order to use the device, the device must be "loaded", i.e. connected to (c) a source of pain relieving drug which, in general, is a potent narcotic drug suspension dispersed within a low boiling point propellant. The entire device is light weight (less than 1 kg loaded) and portable.

A formulation of an analgesic drug in a low boiling point propellant is typically contained in a pressurized canister which is connectable to the "unloaded" device, i.e., the device without the container. When the container of propellant and analgesic drug is connected to the device, the container will include a valve opening at one end which opening is seated into a flow path within the device. The device preferably includes a mouth piece at the end of the flow path, and the patient inhales from the mouth piece which causes an inspiratory flow to be measured within the flow path. This inspiratory flow causes an air flow transducer to generate a signal. This signal is conveyed to a microprocessor which is able to convert, continuously, the signal from the transducer in the inspiratory flow path to a flow rate in liters per minute. The microprocessor can further integrate this continuous air flow rate signal into a representation of cumulative inspiratory volume. At an appropriate point in the inspiratory cycle, the microprocessor can send a signal to an actuation means. When the actuation means is signaled, it releases a valve allowing analgesic drug and propellant to escape into the inspiratory flow path of the device and ultimately into the patient's lungs. After being released, the drug and propellant will preferably pass through -a nozzle prior to entering the inspiratory flow path of the device and thereafter the lungs of the patient.

It is important to note that the firing threshold of the device is not based on a single criterion such as the rate of air flow through the device or a specific time after the patient begins inhalation. The firing threshold is based on an analysis of the patient's inspiratory flow profile. This means that the microprocessor controlling the device takes into consideration the instantaneous air flow rate as well as the cumulative inspiratory flow volume when it determines the optimal point in the patient's inspiratory cycle which would be most preferable in terms of reproducibly delivering the same amount of drug to the patient with each release of drug. Further, the device preferably includes a means for recording a characterization of the inspiratory flow profile for the patient which is possible by including a microprocessor in combination with a read/write memory means and a flow measurement transducer. By using such devices, it is possible to change the firing threshold at any time in response to an analysis of the patient's inspiratory flow profile, and it is also possible to record drug dosing events over time.

Figure 1 shows a cross-sectional view of a hand-held, portable, electronic breath-actuated inhaler device which can be used in connection with the present - invention. The device is shown with a holder 1 having cylindrical side walls and a removable cap. The holder l is "loaded" in that it includes the pressurized canister 3. The canister 3 includes a non-metering valve 5 which is held down in the open position when the cap 2 is screwed down, thus setting the valve 5 into a seat 6 which is in connection with a flow path 8.

A formulation 4 comprised of a narcotic such as sufentanil or fentanyl and a suitable propellant, such as a low boiling point propellant, is contained within the pressurized canister 3. Propellant and narcotic drug are released from the canister 3 via the electrically controlled solenoid 7. In that the valve 5 of the canister is continuously open, another valve, contained within solenoid 7, facilitates the release of the drug. When the solenoid 7 allows release of propellant and drug, the propellant and drug flows through the flow path 8 and then through the solenoid actuated valve 9 into the flow path 10, out through the nozzle 13 and then into the inspiratory flow path 11 surrounded by walls 12.

It is important to note that a variety of devices can be used in order to carry out the pain management delivery methodology of the present invention. However, the device must be capable of allowing the release of a metered amount of analgesic drug based on pre-programmed criteria which are readable by the microprocessor 22. The pre-programmed information is contained within a nonvolatile memory which can be modified via an external device. In another embodiment, this pre-programmed information is contained within a "read only" memory which can be unplugged from the device and replaced with another memory unit containing different programming information. In yet another embodiment, microprocessor 22, containing read only memory which in turn contains the pre-programmed information, is plugged into the device. For each of these three embodiments, changing the programming of the memory device readable by microprocessor 22 will radically change the behavior of the device by causing microprocessor 22 to be programmed in a different manner. As regards the present invention, the non-volatile memory contains information relevant only to the administration of a specific analgesic drug such as fentanyl. Microprocessor 22 sends signals to solenoid 7 which determines the amount of drug delivered into the inspiratory flow path. Further, microprocessor 22 keeps a record of all drug dosing times and amounts using a read/write non-volatile memory which is in turn readable by an external device. The formulation 4 contained within canister 3 is released into the atmosphere ultimately via nozzle 13 which opens into inspiratory flow path 11. It is at this point that the low boiling point propellant within formulation 4 flashes, i.e. rapidly evaporates, thus providing particles of analgesic drug in an aerosol which is introduced into the mouth and ultimately into the lungs of the patient. In order to allow for ease of use, it is possible to form inspiratory flow path 11 into a mouth piece which can be specifically designed to fit the mouth of a particular patient using the device.

The solenoid 7, and associated valve 9, flow paths 8 and 10, as well as nozzle 13 make up the aerosol delivery system 14 shown by the dotted lines within Figure 1. The system 14 is in connection with the flow sensor 15 which is capable of measuring a flow rate of about 0 to about 300 liters per minute. The flow sensor 15 includes screens 16, 17 and 18 which are positioned approximately 1/4" apart from each other. Tubes 19 and 20 open to the area between the screens 16, 17 and 18 with the tubes 19 and 20 being connected to a conventional differential pressure transducer 21. When the user draws air through inspiratory flow path 11, air is passed through the screens 16, 17 and 18 and the air flow can be measured by the differential air pressure transducer 21. The flow sensor 15 is in connection with the aerosol delivery system 14, and when a threshold value of air flow is reached, the aerosol delivery system 14 allows the release of formulation 4 so that a controlled amount of analgesic drug is delivered to the patient. Solenoid 7 is connected to a microprocessor 22 via an electrical connection. The details of the microprocessor and the details of other drug delivery devices which might be used in connection with the present invention are described and disclosed within US patent application 07/664,758, filed on March 5, 1991 entitled "Delivery of Aerosol Medications for Inspiration" which application is incorporated in its entirety herein by reference, and it is specifically incorporated in order to describe and disclose devices as shown within Figure 1 and the microprocessor and program technology used therewith.

A cross-sectional view of yet another (and more preferred) embodiment of the hand-held, electronic, breath-actuated inhaler device of the invention is shown in Figure 2. The device of Figure 2 shows all of the components present within the single hand-held, portable device, i.e. the power source not shown in Figure 1 is shown in the device in Figure 2. Like the device shown within Figure l, the device of Figure 2 includes a canister 3 which includes a canister valve 5. However, unlike the device of Figure l, the device of Figure 2 does not have the valve continuously open but allows a valve 5 connected to the canister 3 to be opened by the mechanical force generated by a valve actuation mechanism 26 which is a motor driven, mechanical mechanism powered by a power source such as batteries 23 and 23'. However, like the device shown within Figure 1, the patient inhales through inspiratory flow path 11 which can form a mouth piece in order to obtain a metering event using the differential pressure transducer 21. Further, when the inspiratory flow meets a threshold of a pre-programmed criteria, the microprocessor 24 sends a signal to an actuator release mechanism 25 which actuates the actuation mechanism 26 forcing canister 3 downward so that canister valve 5 releases formulation into the inspiratory flow path 11. Further details regarding the device of Figure 2 are described within co-pending US patent application entitled "An Automatic Aerosol Medication Delivery System and Methods", filed on January 29, 1993 as Serial No. 08/002,507, which application is incorporated herein by reference in its entirety and specifically incorporated in order to describe and disclose devices as shown within Figure 2 and the microprocessor and program technology used therewith.

Microprocessor 24 of Figure 2 includes an external non-volatile read/write memory subsystem, peripheral devices to support this memory system, reset circuit, a clock oscillator, a data acquisition subsystem and an LCD annunciator subsystem. The discrete components are conventional parts which have input and output pins configured in a conventional manner with the connections being made in accordance with instructions provided by the device manufacturers. The microprocessor used in connection with the device of the invention is designed and programmed specifically so as to provide controlled and repeatable amounts of analgesic drug to a patient upon actuation. Adjustments can be made in the program so that when the patient's inspiratory flow profile is changed such is taken into consideration. This can be done by allowing the patient to inhale through the device as a test in order to measure air flow with preferred drug delivery points determined based on the results of several inhalations by each particular patient. This process can be readily repeated when the inspiratory flow profile is changed for whatever reason, e.g. abdominal incisional pain resulting in low tidal volumes. Determination of optimal drug delivery points in the inspiratory flow can be done at each dosing event, daily, weekly, or with the replacement of a new canister in the device.

The microprocessor of the present invention, along with its associated peripheral devices, can be programmed so as to prevent the release of drug from the canister from occurring more than a given number of times within a given period of time. This feature makes it possible to prevent overdosing the patient with a potent narcotic. The overdose prevention feature can be particularly designed with each individual patient in mind or designed with particular groups of patients in mind. For example, the microprocessor can be programmed so as to prevent the release of more than approximately 200 μg of fentanyl per day when the patient is normally dosed with approximately 100 μg of fentanyl per day. The systems can also be designed so that only a given amount of a particular analgesic drug is provided at a given dosing event. For example, the system can be designed so that only approximately 100 μg of fentanyl is given in a given 15-minute period over which the patient will make approximately 10 inhalations with 10 μg of fentanyl being delivered with each inhalation. By providing this feature, greater assurances are obtained with respect to delivering the analgesic drug gradually over time and thereby providing pain management without overdosing the patient.

Another feature of the device is that it may be programmed to not release drug if it does not receive a signal transmitted to it by a transmitter worn by the intended user. Such a system improves the security of the device and prevents abuse by unauthorized users. The microprocessor of the invention can be connected to external devices permitting external information to be transferred into the microprocessor of the invention and stored within the non-volatile read/ write memory available to the microprocessor. The microprocessor of the invention can then change its drug delivery behavior based on this information transferred from external devices. All of the features of the invention are provided in a portable, programmable, battery-powered, hand-held device for patient use which has a size which compares favorably with existing metered dose inhaler devices. The microprocessor of the present invention is programmed so as to allow for monitoring and recording data from the inspiratory flow monitor without delivering drug. This is done in order to characterize the patient's inspiratory flow profile in a given number of monitoring events, which monitoring events preferably occur prior to dosing events. After carrying out a monitoring event, the preferred point within the inspiratory cycle for drug delivery can be calculated. This calculated point is a function of measured inspiratory flow rate as well as calculated cumulative inspiratory flow volume. This information is stored and used to allow activation of the valve when the inhalation cycle is repeated during the dosing event. The devices of Figures 1 and 2 have been put forth in connection with devices which use a low boiling point propellant and preferably use that propellant in combination with a suspension formulation which includes the dry powdered analgesic drug within the low-boiling-point propellant. Those skilled in the art will readily recognize that such devices can be used for administering a solution of analgesic drug within the low-boiling-point propellant. However, those skilled in the art will also readily recognize that different mechanisms will be necessary in order to deliver different formulations, such as a dry powder without any propellant. A device could be readily designed so as to provide for the mechanical movement of a predetermined amount of dry powder to a given area. The dry powder would be concealed by a gate, which gate would be opened in the same manner described above, i.e., it would be opened when a predetermined flow rate level and cumulative volume have been achieved based on an earlier monitoring event. Patient inhalation would then cause the dry powder to form a dry dust cloud and be inhaled. Dry powder can also be aerosolized by compressed gas, and a solution can be aerosolized by a compressed gas released in a similar manner and then inhaled.

Security Features In that narcotic drugs are subject to drug abuse it is desirable to design devices and methodology so as to hinder abuse to the extent possible. The methodology and devices of the present invention do so in an number of specific ways. The device shown within Figure 2 is designed to be reusable. More specifically, the drug delivery device can be "loaded" with a cassette of the type shown within either of Figures 3 and 4. The cassette is comprised of an outer cover 30, a canister 3 and top nozzle piece 31. The components are shown in a disassembled state in Figure 3. A different embodiment of such components are shown in an assembled state within Figure 4.

In essence, the cassette shown in Figure 3 is somewhat less secure than the cassette shown within Figure 4. As indicated, the top portion of the cover 30 is open within Figure 3. This allows one to force the canister 3 downward and open the valve 5 to allow release of drug. However, in the embodiment shown in Figure 4, there is no general opening but only two small openings 34 and 34'. Using the embodiment shown in Figure 3, the cassette is loaded within the device shown in Figure 2 and a motor driven piston forces the bottom of the canister 3 downward actuating the valve 5 to an open position. In accordance with the embodiment shown within Figure 4, a two-pronged fork device is positioned over the end portion of the cover 30' . Each prong of the fork protrudes through an opening 34 and 34' allowing the canister 3 to be forced downward so that the valve 5 can be opened. It should be pointed out that when the cover 30 is attached to the top nozzle piece 31, they can be sealed together using a fast-acting glue or any appropriate means making it impossible to separate the components. in that the narcotic drug is contained within the canister 3 with a low boiling point propellant it is extremely difficult to open the canister without losing all of the contents. Accordingly, the contents of the canister can generally be obtained only by including the canister within components 30 and 31 and attaching such to the device shown within figure 2.

The following description is provided with respect to Figure 3 and the component shown therein, but is equally applicable with respect to Figure 4 and the component shown therein. The cover 30 can have protuberances such as the protuberance 32 and openings such as the opening 33 thereon. These openings and protuberances can serve as a type of lock and key mechanism which is interactable with receiving protuberances and openings in the device shown in figure 2. Accordingly, unless the cover 30 includes the correct openings and protuberances in the correct position the cover will not fit into the device shown in figure 2 and cannot be -operated. The body of the device as shown within figure 2 is designed so as to be capable of receiving the openings and protuberances on the cover 30. Although devices such as those shown within figure 2 might be utilized to dispense a variety of different types of drugs the physical configuration of the device is specific with respect to certain drugs and is particularly specific with respect to narcotic drugs. Thus, the cover 30 and receiving body portion on the device of figure 2 are designed so that they can be integrated but are also designed so that they will not integrate with other devices not specific for the delivery of narcotic drugs. Thus, as a first layer of security the device and methodology of the present invention provides for a physical lock and key interaction. As a second line of defense against misuse of drugs, it is possible to design the components 31 and 32 and/or the device shown in figure 2 so as to receive a signal from a remote transmitter which is worn by the patient for which the drug was prescribed by the prescribing physician. By designing the device in this manner no drug can be released from the device unless the device is in close proximity to the intended user of the device.

It will, of course, be apparent to those skilled in the art that a combination of all or any of the above security features can be used. Further, the transmitting and receiving signals can be by any means of signalling and need not be limited to radio signals and thus could include infrared and other types of signals. Further, other interlocking mechanisms with more complex physical shapes could be readily devised in order to enhance the security of the device.

As indicated above, the valve actuation means can be electronically prevented from allowing the release of valves. As further indicated above, this is generally done for purposes of security. However, such can also be implemented in order to prevent accidental overdosing by a given patient. For example, the monitoring components of the invention can be designed so as to read the patients respiratory rate. If the respiratory rate is below a given value assigned to the particular patient then the electronics can prevent the release of any drug from the device. It is well known that respiratory rates slow when large amounts of narcotics are administered to a patient. Accordingly, if the patients respiratory rate has been slowed to a dangerously low rate it is important to prevent further administration of drug to the patient.

The instant invention is shown and described herein in which is considered to be the most practical and preferred embodiments. It is recognized, however, that the departures may be made therefrom which are within the scope of the invention and that obvious modifications will occur to one skilled in the art upon reading this disclosure.

Claims

1. A method of intrapulmonary administration of an analgesic drug, comprising: releasing a metered dose of aerosolized analgesic drug from a pressurized canister containing analgesic drug in combination with a low boiling point propellant; inhaling the metered dose of aerosolized analgesic drug into the lungs of a patient.

2. The method of claim 1, further comprising: monitoring the patient's respiratory rate.

3. The method of claim 2, wherein the releasing, inhaling and monitoring steps are continuously repeated in a manner so as to maintain a desired respiratory rate and drug to blood ratio in the patient.

4. The method of claim 1, wherein the releasing is carried out aι_ matically in response to a predetermined measured airflow rate generated by the patient inhaling.

5. The method of claim 4, wherein the releasing is automatically carried out by sending an electronic signal to a valve actuation means which opens a valve in response to a received electronic signal.

6. The method of claim 2, further comprising: measuring the inspiratory flow of the patient and calculating an optimal point in an inhalation cycle based on inspiratory flow rate and cumulative inspiratory volume at which the releasing is to take place.

7. The method of claim 6, further comprising: repeating the measuring, releasing, inhaling and monitoring over a period of time so as to maintain a desired respiratory rate and drug to blood ratio in the patient.

8. The method of claim 1, wherein the analgesic drug is a narcotic.

9. The method of claim 7, wherein the narcotic is selected from the group consisting of fentanyl, sufentanil and morphine.

10. A method of managing a patient's pain, comprising: administering analgesic drug to a patient by an intrapulmonary route, the analgesic drug being administered from a hand-held, self-contained device which releases analgesic drug on detecting a threshold level of inspiratory flow created by patient inhalation.

11. The method of claim 10, further comprising: monitoring patient respiratory rate; and repeating the administering and monitoring steps a plurality of times over a period of time so as to maintain a desired respiratory rate and drug to blood ratio in the patient sufficient to control pain.

12. The method as claimed in claim 10, wherein the amount of analgesic drug administered and the respiratory rate monitored are continually recorded and adjustments are made in the amount of drug administered based on the effect of drug administration on the respiratory rate of the patient.

13. The method as claimed in claim 10, wherein the threshold level of inspiratory flow is determined in a manner so as to maximize repeatability of the amount of analgesic drug delivered to the patient on releasing drug.

14. The method as claimed in claim 10, wherein the analgesic drug is administered in an amount in the range of from about 1 μg to about 100 mg.

15. The method as claimed in claim 10, wherein the analgesic drug is sufentanil.

16. The method as claimed in claim 10, wherein the analgesic drug is selected from the group consisting of fentanyl and morphine.

17. The method as claimed in claim 10, further comprising: orally administering a long acting narcotic to the patient.

18. The method of claim 10, further comprising: transdermally administering an analgesic drug to the patient.

19. The method as claimed in claim 18, wherein the analgesic drag is selected from the group consisting of fentanyl and sufentanil.

20. The method of claim 10, further comprising: monitoring the inspiratory flow of the patient during an inhalation cycle immediately prior to administering the analgesic drug and calculating the threshold level of inspiratory flow prior to administering the drug.

21. The method of claim 20, wherein the monitoring is carried out immediately prior to each dosing event, wherein analgesic drug is administered to the patient and wherein the threshold level is a level calculated to obtain reproducability in the amount of analgesic drug delivered to the patient with each release of drug.

22. A method of managing pain of a patient suffering from pain, comprising: placing a mouthpiece of a hand-held, metered dose inhaler device in the mouth of a patient, wherein the device is comprised of a container having therein analgesic drug and a low boiling point propellant, a valve for releasing analgesic drug and propellant from the container to the -mouthpiece, a means for measuring airflow created by drawing air from the mouthpiece and a means for opening the valve in response to a measured threshold of airflow; drawing air from the mouthpiece until the threshold is reached so as to cause the valve to open and release a controlled amount of analgesic drug and propellant whereby analgesic drug is drawn into the lungs of the patient, wherein the device includes a microprocessor connected to the means for measuring inspiratory flow and means for opening the valve, the microprocessor being programmed to control the amount of analgesic drug released, based on the needs of the patient.

23. A device for the intrapulmonary administration of analgesic drug to a patient, comprising: a canister containing therein analgesic drug and a low boiling point propellant, wherein the analgesic drug and propellant are held within the canister under pressure; a valve for releasing analgesic drug and propellant from the container; a channel which allows released analgesic drug to flow from the valve to a mouthpiece which mouthpiece is in fluid connection with the valve; an airflow detecting means capable of detecting inspiratory flow created by a patient inhaling air through the mouthpiece; a microprocessor programmed to receive data from the airflow detecting means and process the data in a manner so as to determine an optimal point within a patient's respiratory cycle for repeatably delivering the same amount of analgesic drug to the patient at which point the microprocessor sends an electrical signal; and an electronic valve actuation means which opens the valve and releases the analgesic drug and propellant from the container upon receipt of the signal from the microprocessor.

24. The device of claim 23, further comprising: a means for recording information including the time during which the valve is open and calculating valve open time in order to determine the amount of analgesic drug released from the container.

25. The device as claimed in claim 23, further comprising: a signal receiving means and a signal transmitting means, wherein the signal receiving means prevents actuation of the valve for releasing analgesic drug until receiving a signal from the signal transmitting means.

26. The device as claimed in claim 25, wherein the signal transmitting means sends an encoded radio frequency signal and the signal receiving means receives the encoded radio frequency signal.

27. A drug dispensing security system, comprising: a canister containing an analgesic drug and a low boiling point propellant held in the canister under pressure; a valve covering an opening on the canister from which drug and propellant may be released; a valve locking means capable of preventing opening of the valve.

28. The drug dispensing system of claim 27, wherein the valve locking means is maintained in a state so as to lock the valve until the locking means is brought into contact with a valve unlocking means on a drug dispensing device.

29. The drug dispensing system of claim 27, wherein the valve locking means is maintained in a state so as to lock the valve until the locking means receives a radio signal from a valve unlocking signal transmitter.

30. The drug dispensing system of claim 27, wherein the valve locking means is maintained in a state so as to lock the valve until the locking means receives a signal from a respiratory rate monitoring means indicating that a measured respiratory rate is above a predetermined minimum respiratory rate.