EP1124416A1 - Traitement de maux de tete aigus et de douleur chronique au moyen de medicaments anesthesiques rapidement evacues dans des doses subanesthesiques - Google Patents

Traitement de maux de tete aigus et de douleur chronique au moyen de medicaments anesthesiques rapidement evacues dans des doses subanesthesiques

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Publication number
EP1124416A1
EP1124416A1 EP00918120A EP00918120A EP1124416A1 EP 1124416 A1 EP1124416 A1 EP 1124416A1 EP 00918120 A EP00918120 A EP 00918120A EP 00918120 A EP00918120 A EP 00918120A EP 1124416 A1 EP1124416 A1 EP 1124416A1
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pain
patient
anesthetic
drug
propofol
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English (en)
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John Claude Krusz
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    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This invention is in the fields of pharmacology and pain management, and relates to drugs that can stop or reduce pain caused by an acute headache (such as a migraine or cluster headache), or pain of a chronic and intractable type (such as trigeminal facial pain or arachnoiditis).
  • migraines also referred to simply as migraines, for convenience
  • cluster headaches are well-known medical conditions. Extensive background information on them is contained in references such as such as Headache in Clinical Practice (edited by S. Silberstein et al., Oxford Univ. Press, 1998); The Headaches, by J. Olesen; and Headache Disorders: A Management Guide for Practitioners, by A. Rapoport and F. Sheftell (W.B. Saunders, Philadelphia, 1996).
  • triptan drugs that include sumatriptan (sold under trademarks such as IMITREX and IMIGRAN by Glaxo-Wellcome, and also used to treat cluster headaches), naratriptan (sold under the trademarks AMERGE and NARAMIG, also by Glaxo-Wellcome), zolmitriptan (sold under the trademark ZOMIG, by Zeneca Pharmaceuticals), and rizatriptan (sold under the trademark MAXALT, by Merck), there are no adequately safe, rapid, reliable, and satisfactory treatments for recurrent migraines or cluster headaches.
  • sumatriptan sold under trademarks such as IMITREX and IMIGRAN by Glaxo-Wellcome, and also used to treat cluster headaches
  • naratriptan sold under the trademarks AMERGE and NARAMIG, also by Glaxo-Wellcome
  • zolmitriptan sold under the trademark ZOMIG, by Zeneca Pharmaceuticals
  • rizatriptan sold under the trademark MAXALT, by
  • propofol BACKGROUND ON PROPOFOL AND GABA-A RECEPTORS
  • a drug called "propofol” has never been used to treat acute migraine or cluster headaches. It has been used, instead, as an anesthetic or "pre-anesthetic" agent, in conjunction with surgery. Since a new and newly-discovered use for propofol plays a key role in this current invention, this section provides background information on what is already known about propofol, and about the use of propofol as an anesthetic.
  • Propofol is the common chemical name for 2,6-diisopropyl-phenol, which is also called 2,6-bis(l-methylethyl)phenol.
  • a specific formulation containing this active agent in an injectable emulsion is sold in ampules and vials by Zeneca Pharmaceuticals (Wilmington, Delaware), under the trademark DIPRIVAN. It is discussed in various texts such as the Merck Index and the Physicians Desk Reference, and in various published articles cited therein. Additional information on propofol and on the DIPRIVAN formulation is also available via the Internet, at web sites such as www . diprivan . co /PI . html and www . med . umich .
  • DIPRIVAN is a potent anesthetic, and it can be used to rapidly render a patient completely unconscious. Indeed, in some clinical tests, it has been used to keep badly burned patients in an essentially comatose state for weeks at a time, while their burns partially heal. However, because DIPRIVAN contains only 10 mg/mL propofol (about 1 % on a weight/volume basis), it can be administered intravenously at dosages that can be easily titrated for any particular patient.
  • Propofol can strongly decrease respiratory activity and blood pressure. Therefore, it is a potentially dangerous drug which is available by prescription only, and it should be used only in a clinical or hospital setting, under trained care and supervision.
  • Proper equipment and stimulatory drugs (such as norepinephrine) should be immediately available, in case a patient gets too much propofol (or suffers an unexpected adverse reaction to the drug), since it can cause potentially dangerous suppression of respiration or circulation.
  • a patient receiving propofol should be continuously connected to one or more monitors (such as heartbeat, blood pressure monitor, and blood oxygen monitors), which should be equipped with alarms that will sound an alert if the patient's respiration or circulation begin to drop to abnormally low levels.
  • Propofol is known to act as an "agonist" at the "A" subclass of GABA receptors
  • GABA gamma-amino-butyric acid, which is one of the most important inhibitory neurotransmitters in both the brain and the peripheral nervous systems.
  • GABA as an inhibitory (rather than excitatory) neurotransmitter
  • an excitatory neurotransmitter molecule such as glutamate or acetylcholine
  • a neuron into the liquid in a "synapse" (i.e., a transmitting junction between two neurons)
  • the excitatory neurotransmitter molecule contacts and briefly binds to a receptor protein embedded in the synaptic membrane of the signal-receiving neuron. That brief binding reaction causes one or more ion channels which pass through the neuronal membrane to open up for a few milliseconds.
  • the opening of an ion channel through the membrane of the neuron allows one or more types of ions to flow into and out of the neuron, from the extracellular fluid that surrounds the neuron.
  • neurons attain a "ready-to-fire" status when they are in a resting state. This "ready to fire” condition is, in a sense, a high-energy plateau, where an electrochemical voltage of about 65 millivolts (in most CNS neurons; up to about 90 millivolts in other types of peripheral neurons) exists across the neuron's outer membrane.
  • a neuron achieves that resting but polarized condition mainly by pumping sodium and calcium ions (which are positively charged) out of the cell. This voltage differential across the cell membrane also tends to draw chloride ions (which are negatively charged) out of the cell, into the positively charged fluid that surrounds the cell.
  • excitatory receptors in a synapse When excitatory receptors in a synapse are triggered, they open up one or more ion channels across the cell membrane. These ion channels allow ions to flow into and out of the neuron. If enough channels are opened during a brief span of time, a "depolarizing" event occurs, which is interpreted and processed by the neuron as a "firing" event. The neuron then carries out two functions: (i) it releases some of its own neurotransmitter molecules into other synapses, thereby passing on the nerve signal to other neurons, and (ii) it closes its ion channels and quickly begins pumping ions back across the outer membrane to regain its polarized "ready-to-fire” status again, so it will be ready to receive and process the next arriving nerve impulse.
  • inhibitory neurotransmitters In contrast to excitatory neurotransmitters, inhibitory neurotransmitters (such as GABA) have an opposing effect on neuronal firing. If a molecule of GABA contacts and reacts with a GABA receptor on a neuron, the reaction between the GABA molecule and the GABA receptor causes that neuron to become less susceptible to being triggered and fired by excitatory events.
  • GABA GABA
  • GABA performs this function by opening (and keeping open, for some period of time) a chloride ion channel which passes through the neuronal membrane. This opening of chloride ion channels alters the polarized status of the neuron, which in turn reduces the ability and readiness of the GABA-inhibited neuron to go through the various steps of a firing (depolarization) event.
  • a chloride ion channel which passes through the neuronal membrane.
  • This opening of chloride ion channels alters the polarized status of the neuron, which in turn reduces the ability and readiness of the GABA-inhibited neuron to go through the various steps of a firing (depolarization) event.
  • the GABA-inhibited neuron will be less ready, and less able, to pass the incoming nerve signal on, to other neurons.
  • Inhibitory neurotransmitters are extremely important to the functioning of the central and peripheral nervous systems. They can be compared to the tuning components in a radio or television set. If a radio does not have a properly working tuner, and plays any and all signals it receives, the result will be a chaotic, jumbled, uncoordinated mix of dozens of different and competing signals. In order for a radio or television to work properly, it must be able to receive and properly process the signals that are arriving on just one channel at a time, while suppressing and filtering out competing signals from all other channels.
  • the brain uses inhibitory neurotransmitters such as GABA to help it filter out and regulate unwanted and distracting nerve impulses.
  • inhibitory neurotransmitters such as dopamine and serotonin
  • Drugs that interact with dopamine or serotonin receptors tend to be psychoactive drugs; they do not render a patient numb or unconscious, and are used instead for treating various mental states (depression, psychosis, etc.) rather than as sedatives or anesthetics.
  • GABA is a potent inhibitory neurotransmitter, which can inhibit nerve impulses to the point of completely blocking and preventing the transmission of nerve impulses.
  • GABA agonists can be used as sedatives and anesthetics; they can render a patient completely unconscious during surgery. Most of the powerful barbiturates and anesthetics that can render someone totally unconscious are GABA agonists.
  • propofol is known to be a GABA agonist, and it can quickly render someone totally unconscious, in suitable dosages. It is often used as an initial or
  • pre-anesthetic agent to heavily sedate patients who are about to be taken into surgery. After the patient enters the operating room, the use of propofol (which is relatively expensive) is often discontinued, and a gaseous agent such as isoflurane, enflurane, or sevoflurane (which are less expensive than propofol) is usually administered as the main anesthetic drug.
  • a gaseous agent such as isoflurane, enflurane, or sevoflurane (which are less expensive than propofol) is usually administered as the main anesthetic drug.
  • GABA-A receptors A receptors, referred to herein as GABA-A receptors.
  • GABA-A receptors are a complex topic in their own right, and there are multiple subtypes of GABA-A receptors.
  • a typical GABA-A receptor complex is made up of 5 different protein subunits; however, at least 6 different protein subunits have been identified, and different GABA-A receptor subtypes are made up of varying combinations of those subunits.
  • GABA receptors see, e.g., Barnard et al 1998, Costa et al 1998, Korpi et al 1997, and Avoli et al 1997.
  • propofol can be administered for surgical anesthesia purposes as an inhalable gaseous agent; see US 5,496,537 (Henry 1996), using certain types of hydrofluorocarbon propellants, such as 1 , 1 , 1 ,2-tetrafluoroethane or
  • GABA-A anesthetics including isoflurane, enflurane, and sevoflurane
  • GABA-A anesthetics are also volatile gases, which are administered by inhalation rather than intravenous injection.
  • any such gaseous GABA-A anesthetics can be evaluated for potential use as disclosed herein, if desired, to avoid the need for needlesticks when intravenous injection is involved. It should be recognized that under standard practices for surgical anesthesia, an intravenous line is almost always established before an inhalable gas is used, so that if a patient goes into a severe respiratory or circulatory depression or collapse, the already-established intravenous line can be used immediately for emergency injection of stimulant drugs. However, since the new uses disclosed herein involve "sub-anesthetic" dosages which preferably never cause any loss of consciousness, any attendant risks should be very small.
  • one object of this invention is to disclose and provide a method for treating an acute migraine, cluster, or other severe headache, to reduce or entirely stop the pain caused by the headache.
  • Another object of this invention is to disclose and provide a rapid and highly effective method for treating a migraine, cluster, or other acute headache, in a manner which provides a highly effective treatment with virtually no adverse side effects or lingering after-effects (such as drowsiness, grogginess, disorientation, nausea, or other such problems), thereby allowing the patient to be ready and able to drive, work, or carry out any other normal activity within an hour after such treatment is commenced.
  • Another object of this invention is to disclose and provide a method for aborting and preventing migraine, cluster, or other acute headaches, as soon the symptoms of an approaching headache begin to appear in a patient.
  • Another object of this invention is to disclose and provide a method for treating chronic and/or intractable pain, such as trigeminal facial pain, arachnoiditis, etc.
  • a method for using a rapidly-cleared anesthetic drug, such as propofol, to treat acute migraine headaches, cluster headaches, and other acute headaches is disclosed.
  • a rapidly-cleared anesthetic drug such as propofol
  • propofol an anesthetic drug normally used for surgery
  • a feeling of sedated relaxation without loss of consciousness can interrupt and effectively stop a "runaway pain" condition such as a migraine or cluster headache.
  • This invention discloses a method for using a "rapidly- cleared anesthetic drug" to treat acute migraine headaches, cluster headaches, or other severe headaches, and for treating chronic and/or intractable pain, as discussed below.
  • rapidly-cleared anesthetic drug refers to a drug, such as propofol or a suitable analog thereof, which has both of the following characteristics: (1) it must have a half-life, in circulating blood in typical human patients, of about 30 minutes or less; and (2) it must be pharmacologically acceptable and effective as an anesthetic drug, as that term is conventionally used by physicians and pharmacologists.
  • an anesthetic drug is a drug which depresses nerve function, leading to a loss of sensation.
  • an anesthetic drug is a drug that causes drowsiness, sleepiness, or a similar hypnotic or dissociated mental state, if administered in a manner that causes the drug to reach the brain.
  • Some but not all anesthetic drugs can also cause a localized feeling of numbness or loss of sensation in a particular part of the body (such as a limb or extremity), if administered locally.
  • anesthetic drugs can cause analgesic activity (i.e., pain-reducing activity).
  • analgesic activity i.e., pain-reducing activity
  • pain-reducing drugs such as aspirin, acetaminophen, and ibuprofen are analgesics (pain-killers), but not anesthetics.
  • anesthesia by itself, even at levels that lead to apparently total unconsciousness of a patient, does not imply an absence of pain.
  • a patient who is under general anesthesia during surgery usually needs to be treated with both an anesthetic, and an analgesic.
  • Use of an anesthetic without accompanying analgesia can lead to highly adverse symptoms such as severe muscle twitching and the release of distress-signalling hormones in the body of the unconscious patient.
  • propofol sold as an injectable liquid formulation under the trademark DIPRIVAN by Zeneca Pharmaceuticals (Wilmington, Delaware), falls squarely within the term, "rapidly-cleared anesthetic drug” as used herein, and it was used in all tests described in the Examples.
  • the full chemical name of propofol is 2,6-diisopropylphenol; that same chemical is also known as 2,6-bis(l-methylethyl)phenol.
  • the active ingredient propofol is highly oleophilic (hydrophobic), and does not dissolve easily in water; accordingly, the DIPRIVAN formulation is an injectable emulsion.
  • propofol can also be administered as an inhalable gas, without requiring an intravenous puncture.
  • Example 1 intravenous injection of DIPRIVAN was tested as a treatment for acute headaches on 53 patients who appeared, seeking medical treatment, at the Anodyne PainCare Clinic in Dallas, Texas, which is run by the Applicant herein, John Claude Krusz, Ph.D., M.D. , who specializes in treating acute headaches and other types of chronic and intractable pain. Most of the 53 patients treated with DIPRT AN had headaches that were diagnosed as migraine headaches, but one patient suffered from cluster headaches instead, as described in Example 2. The tests disclosed in the Examples did not use blinded treatment procedures or untreated control populations; instead, each patient was informed in advance of the proposed treatment, and gave fully informed consent. The dosages of DIPRIVAN administered to such patients was well within the
  • sub-anesthetic range in which the patient does not lose consciousness.
  • an initial dosage of 2 to 3 ml was administered as an initial bolus, and the patient then reported orally to the doctor or other attendant on his or her condition and pain status. Additional sequential boluses of 2 to 3 ml were then administered, until the patient reported satisfactory resolution of the headache pain.
  • this invention preferably does not involve sustained infusion of an anesthetic drug into a patient. Instead, it preferably should involve a relatively brief administration (such as an intravenous injection lasting about 45 minutes or less, or a relatively brief inhalation session) that is done under the care of a physician, nurse, or physician's assistant, in a manner which takes the patient to a point of highly relaxed and essentially pain-free sedation which stops short of unconsciousness or sleep.
  • a relatively brief administration such as an intravenous injection lasting about 45 minutes or less, or a relatively brief inhalation session
  • the physician or assistant should be able to communicate with the patient throughout the entire procedure.
  • the patient yields (usually quite honest) to a sense of relaxation and relief, which is aided and intensified by the fact that an acute migraine headache or other such pain begins to rapidly disappear as the drug takes over. If and when the pain completely subsides, the infusion is terminated, and the patient will quickly regain full and alert consciousness, usually within about 10 to 15 minutes.
  • this invention discloses a method for treating acute headache pain, comprising the following steps: (A) administering, to a patient who is suffering from an acute headache, a rapidly-cleared anesthetic drug (such as propofol, in a suitable injectable or inhalable formulation) which penetrates mammalian blood-brain barriers, agonizes GABA-A neuronal receptors, and has a half-life in circulating blood of about 30 minutes or less, at an effective dosage which induces a relaxed or hypnotic state without causing a loss of consciousness; (B) monitoring the patient's condition to determine when the drug has reduced the acute headache pain to a level that is acceptable to the patient; and, (C) terminating administration of the drug, in a manner which allows the patient to regain alert consciousness without causing the pain to return.
  • a rapidly-cleared anesthetic drug such as propofol, in a suitable injectable or inhalable formulation
  • this invention discloses a method for preventing emergence of acute headache pain, in a patient who suffers from repetitive acute headaches (such as migraine or cluster headaches) without such treatment.
  • This method of aborting a headache, before it becomes acute is performed on a patient who is experiencing symptoms which indicate the "onset" (i.e., the approach, emergence, or other development or impending arrival) of acute headache pain, before the pain becomes acute.
  • This method comprises the step of administering to the patient a rapidly-cleared anesthetic drug (such as propofol), at an effective dosage which prevents the onset of acute headache pain.
  • a rapidly-cleared anesthetic drug such as propofol
  • the Applicant a medical doctor and his assistants who have carried out or witnessed this treatment on people who were suffering from extremely intense and acute migraine headaches usually compare the results of this treatment to stopping a runaway horse, or a runaway train.
  • This may help describe and explain the ability of a rapidly-acting, rapidly-cleared anesthetic drug to provide lasting relief from acute pain. If a horse has been badly spooked and frightened, it will launch into a "panicked gallop" mode, where it tries to get away from something, as fast as possible, by running just as hard as it possibly can.
  • a runaway train has a huge load of inertia, if it is barrelling down a railroad track at top speed. However, if that train can be completely stopped somehow, even for just a moment, all of that inertia disappears. Once it is at rest, stationary, it would take a very large amount of work to get it running fast again. In an analogous manner, it appears that migraine and cluster headaches (and various other types of acute or intractable pain) are caused or aggravated, in at least some patients, by one or more "runaway" physiological conditions.
  • a "vicious circle” is commenced, in which an initial triggering factor leads to an initial physiological response (such as release of histamines, interleukins, lymphokines, stress hormones, Substance P, etc., by certain cells or tissues).
  • This physiological response triggers one or more subsequent cellular or physiological responses (such as blood vessel dilation or constriction, inflammation of a particular tissue type, etc.).
  • This secondary adverse response then aggravates and increases the initial mediating physiological response, thereby causing even more histamines, interleukins, lymphokines, stress hormones, and Substance P to be dumped into the system. This makes things even worse, and further aggravates the secondary adverse response.
  • That type of "vicious circle” can turn into an out-of-control cascade, comparable to a rockslide or an avalanche that keeps gaining more and more speed and momentum as it keeps rolling farther and faster down a slope.
  • This out-of-control process can lead to the types of excruciating pain and agony that are all too familiar to people who suffer from acute migraines and cluster headaches, and to others who suffer from acute intractable pain.
  • homeostasis refers to a type of dynamic and adaptive equilibrium which relies heavily on various feedback and control systems, which allows a complex animal with numerous internal organs (all of which must, in a sense, compete against each other for the limited supply of oxygen and nutrients carried by the blood) to remain alive and healthy.
  • Homeostasis is a dynamic, constantly changing, highly adaptive process in any living animal; it has to be, since the surrounding environment and numerous impinging factors (including the digestive, exercise, and respiratory states of an animal's body, as well as the status of billions of both benevolent and pathogenic microbes that inhabit that animal at any given moment) are constantly changing.
  • impinging factors including the digestive, exercise, and respiratory states of an animal's body, as well as the status of billions of both benevolent and pathogenic microbes that inhabit that animal at any given moment.
  • a migraine headache is likened to a runaway horse which has launched itself into an out-of-control panicked gallop
  • the brain and body will begin attempting to exert control over that runaway condition, trying to bring it back under control.
  • the brain and body will begin trying to reestablish that type of control, on their own, using natural feedback mechanisms, before any drug intervention is commenced.
  • treatment with a rapid-acting and rapidly- cleared anesthetic drug such as propofol or a suitable analog thereof, can provide a potent method for, in effect, lassoing and stopping a runaway horse, for a few minutes.
  • This intervention which forces the runaway horse to stop for a while, allows the regulatory mechanisms of the brain and body (which have already been fully switched on, by the onset of acute pain from a migraine headache) to respond in whatever way is necessary for them to reestablish control. Those mechanisms can then reestablish full and proper control of the system, in a manner similar to a skilled horse trainer who knows how to calm down and control a tired horse.
  • this invention involves the use of "rapidly-cleared anesthetic drugs" to treat acute migraine headaches, cluster headaches, or other severe headaches.
  • propofol in an injectable formulation such as DIPRIVAN, appears to have an ideal combination of properties and activities for such use, this invention is not limited to the use of propofol, or of the DIPRIVAN formulation.
  • various analogs and congeners of propofol are known to have anesthetic properties. A number of such analogs and congeners are listed and described in Trapani et al 1998. Any such analog, congener, isomer, or derivative of propofol which is pharmacologically acceptable, and which has anesthetic properties, can be evaluated for use as described herein, using no more than routine experimentation.
  • salts, isomers, analogs, and derivatives which are not listed in Trapani et al 1998 can also be tested for use as disclosed herein, provided that such salts, isomers, analogs, or derivatives are: (1) pharmacologically acceptable; (2) functionally effective as anesthetic drugs which act as agonists at GABA-A receptors; and (3) rapidly cleared from circulating blood, with a half life of about 30 minutes or less in circulating blood.
  • a halogen atom might be used instead of the hydroxy group, in the phenol precursor; such compounds were not tested by Trapani et al.
  • substituents when coupled to benzene rings, act as "ortho, para- directing groups" that cause additional substitution reactions to predominately or exclusive involve the "ortho" and "para" carbon atoms in the benzene ring.
  • isobutyl groups or larger branched alkyl groups might be used in place of either or both of the isopropyl groups coupled to the benzene ring.
  • isobutyl groups or larger branched alkyl groups might be used in place of either or both of the isopropyl groups coupled to the benzene ring.
  • the term "pharmacologically acceptable” embraces those characteristics which make a drug suitable and practical for administration to humans. For example, such compounds must be sufficiently chemically stable under reasonable storage conditions to have an adequate shelf life, and they must be physiologically acceptable when introduced into the body by a suitable route of administration.
  • the term “analog” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a referent molecule (2,6-diisopropylphenol, in this case) but which has been modified in a targeted and controlled manner to replace a specific substituent of the referent molecule with an alternate substituent.
  • derivative refers to a molecule that is obtained by using 2,6-diisopropylphenol as a starting compound, and then modifying it in a controlled manner which generates a compound that has the desired traits of a pharmacologically acceptable anesthetic drug which is rapidly cleared from circulating blood.
  • Administration of the compounds of this invention can use any acceptable technique that is capable of introducing the compounds into the bloodstream.
  • Intravenous injection is currently the standard method of administration, since the only formulations of propofol that have been fully approved for human use are injectable emulsions.
  • propofol also appears to be well-suited for administration as an inhalable gas.
  • various propellants other than the fluorocarbons listed in US 5,496,537 can also be evaluated, if desired.
  • a second type of volatile anesthetic called cyclopropane may be useful as both a propellant and an adjunctive anesthetic, for the purposes disclosed herein. Since cyclopropane is highly flammable and potentially explosive, it cannot be used in conjunction with electrical cautery, and it has therefore has fallen into disfavor as an anesthetic during surgery, since cautery is so widely used.
  • cyclopropane might be useful as a propellant and/or adjunctive agent for propofol or other gaseous anesthetics, for use as disclosed herein.
  • this invention discloses a composition of matter, comprising an inhalable gaseous mixture containing (i) a first anesthetic drug selected from the group consisting of propofol, and salts, isomers, analogs, and derivatives of propofol which are pharmacologically acceptable as inhalable anesthetic agents, and (ii) a second anesthetic drug comprising cyclopropane, wherein the first and second anesthetic drugs are present in the inhalable gaseous mixture at therapeutically effective concentrations which allow the inhalable gaseous mixture to be used in inhalant form to treat acute headache pain without rendering a patient unconscious.
  • a first anesthetic drug selected from the group consisting of propofol, and salts, isomers, analogs, and derivatives of propofol which are pharmacologically acceptable as inhalable anesthetic agents
  • a second anesthetic drug comprising cyclopropane
  • This invention also discloses an article of manufacture, comprising (a) a container for holding a pressurized inhalable gaseous mixture, (b) a pressurized inhalable gaseous mixture contained within such container; and (c) outlet means which enable administration of the gaseous mixture to a human patient, wherein the gaseous mixture comprises (i) a first anesthetic drug selected from the group consisting of propofol, and salts, isomers, analogs, and derivatives of propofol which are pharmacologically acceptable as inhalable anesthetic agents, and (ii) a second anesthetic drug comprising cyclopropane, and wherein the container and outlet means act together to allow the gaseous mixture to be used to treat acute headache pain in a human patient without rendering the patient unconscious.
  • a first anesthetic drug selected from the group consisting of propofol, and salts, isomers, analogs, and derivatives of propofol which are pharmacologically acceptable as inhalable an
  • anesthetics In addition to propofol and its analogs, various other agents are known to act as anesthetics, and most such anesthetics usually have some level of agonist activity at GABA- A receptors; such drugs include volatile gases (such as isoflurane, enflurane, and sevoflurane; see, e.g., Krasowski et al 1998) and various barbiturate drugs (see, e.g., Davies et al 1998). Any such anesthetic drug which has a relatively short half-life (such as about 30 minutes or less; drugs having a half life of about 10 minutes or less are preferred) in circulating blood can be evaluated for use as a treatment for acute headaches, using the methods disclosed herein, with no more than routine experimentation.
  • volatile gases such as isoflurane, enflurane, and sevoflurane
  • barbiturate drugs see, e.g., Davies et al 1998.
  • a volatile gas anesthetic is evaluated for potential use as disclosed herein, to determine whether it can be used safely without requiring an intravenous needlestick, it should be recognized that under standard anesthetic practices, an intravenous line is almost always established before an inhalable gas is used. This is a standard safety precaution, so that if a patient goes into a severe respiratory or circulatory depression or collapse, the already-established intravenous line can be used immediately for emergency injection of stimulant drugs.
  • testing may indicate that relatively low sub-anesthetic concentrations and/or dosages may be used safely without requiring an intravenous line as a routine precaution, so long as emergency treatment is immediately available if it becomes necessary.
  • rapidly-cleared anesthetic drugs can be used to treat any type of acute headache, either after the headache has emerged in full and acute form, or at any time after one or more "early onset" symptoms begin to arise.
  • Such agents can be used alone or in combination, in concentrations and dosages that can be evaluated for any type or severity of headache, using no more than routine experimentation, guided throughout the course of treatment of any particular patient by the spoken comments of the patient, who can provide a continuous status report on the progress of the treatment, without ever losing consciousness.
  • This invention also discloses an article of manufacture, comprising a vial which contains a sterile quantity of propofol (or another suitable rapidly-cleared anesthetic drug) which is not sufficient for surgical anesthesia, but which is well-suited for treating a migraine or cluster headache.
  • Vials of DIPRIVAN that are sold for surgical anesthesia contain 20 ml of the injectable emulsion. Each ml of emulsion contains 10 mg of propofol; accordingly, a vial that has been manufactured for surgical anesthesia purposes contains 200 mg of propofol. That is roughly twice as much propofol as is necessary to treat, quite adequately, a large majority of acute migraine and cluster headaches. Based on the results of tests involving 45 patients, as disclosed in Example 1, it appears that about 80% of all such headaches were fully resolved (i.e. , 100% pain relief) by administration of 100 mg or less of propofol (i.e. , using only half the surgical dosage of propofol). About 95% of all such headaches were fully resolved (with 100% pain relief) when slightly higher quantities (up to about 140 mg propofol) were administered.
  • this invention discloses and claims vials that contain a total quantity of a rapidly-cleared anesthetic drug (such as propofol or a suitable analog thereof), in a "sub-anesthetic dosage" (i.e., a dosage which is not adequate to establish complete surgical anesthesia, but which is adequate for providing complete relief from pain in at least
  • this "sub-anesthetic" dosage covers a vial or ampule containing about 100 mg up to about 150 mg propofol.
  • the cost of vials for treating headaches can be reduced compared to the costs of vials with a full 200 mg, as used for surgical anesthesia.
  • vials containing "sub-anesthetic dosages" (about 100 to 150 mg) of propofol have never previously been manufactured and sold.
  • Treatment using a rapidly-cleared anesthetic drug such as propofol
  • Tests using propofol to treat trigeminal pain facial or arachnoiditis, with highly successful outcomes, are described in Example 3 and 4.
  • Chronic refractory and/or intractable pain that are likely to be relieved substantially in at least some patients include (1) phantom limb pain suffered by an amputee; (2) a condition known to physicians as "complex regional pain syndrome"; (3) post-operative pain that has persisted for longer than a month following a surgical operation; (4) pain caused by herpes zoster viruses, in a condition widely known as shingles; and (5) pain caused by certain types of bone degenerative diseases. It also is recognized by the Applicant that a combined treatment regimen using a rapidly-cleared anesthetic such as propofol is likely to offer an improved treatment for neuropathic pain in many patients.
  • a rapidly-cleared anesthetic such as propofol
  • neuroopathic pain refers to pain that is not adequately blocked by opiate- type drugs.
  • the improved treatment contemplated by the Applicant uses both: (i) initial treatment (and possibly periodic and/or as-needed treatment) with a rapidly-cleared anesthetic drug such as propofol; and, (ii) daily or other chronic treatment using other drugs, such as carbamazepine (TEGRETOLTM), gabapentin (NEURONTINTM), amitriptyline (ELAVILTM), topiramate (TOPAMAXTM), lamotrigine (LAMICTALTM), or tiagabine (GABITRILTM), or a drug that suppresses activity at the NMDA class of glutamate receptors.
  • TAGRETOLTM carbamazepine
  • NEURONTINTM gabapentin
  • ELAVILTM amitriptyline
  • TOPAMAXTM topiramate
  • LAMICTALTM lamotrigine
  • GABITRILTM tiagabine
  • NMDA antagonist drugs for treating neuropathic pain is discussed in various patents and other publications; see, e.g., US patents US 5,605,911 (Olney 1997), and 5,629,307 (Olney 1997).
  • Long-term treatment of a chronic and intractable pain condition, using drugs such as these, may be substantially improved if a rapid-acting anesthetic drug such as propofol is used first, at subanesthetic doses, to provide immediate short-term relief from the pain. This would, in effect, allow a chronically administered drug to start from a "ground zero" condition, instead of having to first treat an acute pain condition and then provide lasting relief.
  • the current emulsified formulation reportedly contains, in addition to propofol as the active agent, soybean oil (100 mg/mL), glycerol (22.5 mg/mL), and egg lecithin (12 mg/mL), with sodium hydroxide to adjust pH (Physicians Desk Reference, 50th Edition, 1996). Recently, disodium edetate has been added to the formulation, to retard the risk of microbial growth. Other efforts are also being made to develop and test other types of preservatives as well.
  • the standard emulsified formulation reportedly can cause pain at the site of injection, in at least some patients (e.g., Tan et al 1998; Uda et al 1998; Ozturk et al 1998).
  • many physicians have adopted a practice of mixing a small quantity of lidocaine in with the DIPRIVAN formulation, so that both the DIPRIVAN and the lidocaine are mixed together in a saline carrier solution.
  • a person who suffers from frequent migraine or cluster headaches may receive a much higher number of propofol injections than someone who is only injected a few times during his/her lifetime, in conjunction with surgery.
  • an injected formulation containing a soy product and an egg product may raise a concern over a possible allergic response.
  • DIPRIVAN formulation such as soybean oil or egg lecithin
  • any such formulation would be likely to contain water, and would likely be in the form of an emulsion, since propofol is strongly oleophilic.
  • One or more synthetic organic compounds having a plurality of hydroxyl groups can be used as an emulsifying agent; various compounds such as propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, dextran compounds, and/or cyclodextrin compounds are often used in such formulations.
  • a buffering or neutralizing compound, and possibly an antimicrobial agent, can also be used in such a formulation.
  • any problems that accompany intravenous injection of propofol can likely be avoided by development of one or more formulations that can be administered by means other than intravenous injection.
  • One such class of formulations includes inhalable gaseous formulations, as disclosed in US 5,496,537 (Henry, 1996).
  • Transdermal delivery systems can use any of a number of known permeable polymers, porous fabrics, or other suitable materials that can release suitable quantities of a drug; one example of such a polymer is disclosed in US patent 4,563,184 (Korol 1986).
  • the quantity of such a drug which reaches and enters circulating blood via a transdermal delivery mode can also be increased by various means, such as (i) by applying heat to the patch, such as by using a heating pad, a compress soaked in hot water, etc., and/or by mixing the pain-reducing drug with a carrier agent that enhances permeation and delivery, such as dimethyl sulfoxide (DMSO).
  • a carrier agent that enhances permeation and delivery such as dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Still other known modes of administration also can be evaluated for use as disclosed herein; such modes include rectal suppositories, troches, etc.
  • two or more modes of administration can be used in conjunction with each other, to treat acute headaches or other forms of acute pain.
  • a patient suffering from frequent (such as daily) cluster headaches could be treated by using an injectable or inhalable formulation in an initial treatment, followed by a skin patch, rectal suppository, or other delivery mode that can continue to release a drug over a period of 48 to 72 hours.
  • Example 1 Treatment of Acute Migraine Headaches
  • DIPRIVAN an injectable emulsion containing 1 % w/v propofol
  • Trigeminal pain is widely regarded as one of the most difficult forms of pain to treat effectively without putting a patient into a heavily drugged state using a powerful narcotic or barbiturate drug.
  • Both patients with trigeminal pain were treated essentially as described above, using repeated small (usually 2 to 3 ml) bolus injections of DIPRIVAN, followed by a subsequent 15 oral report from the patient to the attending physician on the severity of the pain, before another small bolus was administered.
  • Each patient eventually received a total of about 20 to 24 ml of DIPRIVAN, over a span of about 45 minutes.
  • a patient who had received a series of back surgeries following a severe automobile accident was diagnosed by the Applicant as suffering from arachnoiditis.
  • the patient was treated using small bolus injections of DIPRIVAN, as described above, and reported nearly 30 100% pain reduction, which was better than he had ever received before, from any other type of medication.
  • GABA-A receptors expressed in Xenopus oocytes influence of alpha and gamma-2 subunits, " Brain Research 784: 179-187 (1998)

Abstract

Selon cette invention, on peut utiliser un médicament anesthésique rapidement évacué tel que le propofol pour traiter la migraine, la céphalée vasculaire de Horton ou d'autres états de 'douleur qui s'emballe'. Utilisé dans un dosage subanesthésique qui ne provoque pas de perte de connaissance, le propofol (médicament employé en anesthésie chirurgicale et qui doit être injecté mais peut aussi être inhalé) crée par son effet sédatif une sensation de relaxation. Cet état sédatif de relaxation peut bloquer et même faire cesser la 'douleur qui s'emballe', par exemple, la migraine ou la céphalée vasculaire de Horton, ainsi que de différents types de douleurs chroniques intraitables tels que le tic douloureux de la face ou l'arachnoïdite. Dans les cas types du traitement, on a utilisé de 2 à 3 ml au début suivis de bols de 2 à 3 ml supplémentaires espacés dans le temps, en fonction de l'état de la douleur dont souffre le patient. Lorsqu'on atteint le niveau désiré de l'effet sédatif et que le patient annonce que la douleur a cessé, on arrête l'administration du médicament. Le médicament doit être rapidement métabolisé et éliminé du sang de manière à ce que les patients retrouvent rapidement un état actif et alerte (normalement après 5 à 10 minutes dans le cas du propofol) et puissent quitter la clinique en toute sécurité au volant de leur voiture pour retourner au travail ou à d'autres occupations usuelles, et ce sans éprouver d'effets secondaires désagréables ou d'effets postérieurs résiduels. Lors des tests effectués avec des patients souffrant de la migraine aiguë ou de la céphalée vasculaire de Horton, la plupart ont remarqué un soulagement à 100 % et n'ont éprouvé aucun mal de tête de rebond le lendemain. Dans le cas des patients souffrant de douleur chronique intraitable, le traitement au propofol a normalement apporté un soulagement efficace de la douleur pendant 3 à 5 jours avant qu'un nouveau traitement ne fût nécessaire.
EP00918120A 1999-03-15 2000-03-15 Traitement de maux de tete aigus et de douleur chronique au moyen de medicaments anesthesiques rapidement evacues dans des doses subanesthesiques Withdrawn EP1124416A1 (fr)

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