EP0854713A1

EP0854713A1 - Compositions of melatonin and analgetic agents and methods of use thereof

Info

Publication number: EP0854713A1
Application number: EP95933966A
Authority: EP
Inventors: Richard J. Wurtman
Original assignee: Interneuron Pharmaceuticals Inc
Current assignee: Indevus Pharmaceuticals Inc
Priority date: 1995-10-03
Filing date: 1995-10-03
Publication date: 1998-07-29
Also published as: EP0854713A4; CA2231557A1; WO1997012612A1

Abstract

Compositions comprising melatonin and one or more analgetic agents and methods of administering melatonin and one or more analgetic agents to relieve pain and induce sleep are described.

Description

COMPOSITIONS OF MELATONIN AND ANALGETIC AGENTS AND METHODS OF USE THEREOF

Background

Analgetic agents, particularly non-narcotic analgetic agents, are administered to individuals as treatment for pain. Most commonly used analgetic agents include aspirin and aspirin-like compounds, frequently termed non-steroidal anti-inflammatory drugs (also referred to as NSAIDs) . Although the effectiveness of these analgetic agents to relieve pain is well-known, other physiological effects resulting from the administration of analgesics often occur. For example, treatment of pain with analgetic agents often results in loss of sleep. Thus, individuals experiencing pain at night may find their sleep patterns seriously disrupted after taking an analgesic, even though they no longer experience pain. Such individuals are often subjected to hypnotic drugs, such as a benzodiazepine, or antihistamine agents, such as diphenhydramine hydrochloride, to induce sleep. Benzodiazepines have the disadvantage of being addictive, and in addition, individuals taking these drugs often experience residual amnesic effects for a period of time. Although antihistamines may make an individual drowsy, they also have the disadvantage of producing non-specific antihistaminic effects in an individual who is not in need of such effects. Thus, it would be advantageous to have available a composition which provides pain relief and induces sleep without producing such unwanted side-effects. Summary of the Invention

The present invention relates to compositions comprising melatonin and one or more non-narcotic analgetic agents. Such compositions provide an individual with effective pain relief while reducing, partially or totally, disruption of normal nighttime sleep patterns. The present invention also relates to methods of relieving pain, fever and inflammation while inducing sleep by administering a composition comprising melatonin and one or more non-narcotic analgetic agents.

Analgetic agents are administered for analgesic

(pain-killing) relief. Commonly used non-narcotic analgetic agents include aspirin and non-steroidal anti- inflammatory drugs (NSAIDs) , such as acetaminophen and ibuprofen. However, aspirin and NSAIDs, in addition to their known pain relieving properties, are also known to disrupt sleep in mammals. Recent studies have indicated that the administration of a non-narcotic analgetic agent leads to suppression of the normal nocturnal surge in the synthesis of melatonin, which has sleep-inducing properties resulting in the disruption of normal sleep patterns. Murphy, P.J., et al. , Physiol. & Behavior. 55(6) : 1063-1066 (1994) . Thus, individuals taking non-narcotic pain relief medication often experience severe difficulty in falling asleep.

The present invention is based on Applicant's discovery that the administration of an effective dose of a non-narcotic analgetic agent with an effective dose of exogenous melatonin reduces, partially or totally, the sleep disruption that often accompanies the administration of analgetic agents. The administration of melatonin provides an effective means of inducing sleep by restoring endogenous serum melatonin to levels sufficient to induce sleep in the individual, even in the presence of the analgesic. Methods of administering the compositions comprising melatonin and one or more analgesic agents, as described herein, include administration of the compositions up to four hours, preferably up to two hours, before an individual desires to fall asleep, or at four-hour intervals if the individual awakens and desires to resume sleeping. In a preferred embodiment of this invention, the compositions are administered orally (ingested) or transdermally. The compositions of the present invention are effective to alleviate or significantly reduce pain in an individual desiring sleep and seeking relief from pain without the accompanying sleep loss often associated with therapeutic doses of analgetic agents. Furthermore, the use of melatonin to induce sleep has a number of advantages over conventional hypnotic drugs, such as benzodiazepines. Melatonin is naturally metabolized within hours of administration. Thus, methods of inducing sleep using melatonin do not produce adverse residual effects the day following administration, as do conventional hypnotics. Additionally, the compositions of the present invention also lack the undesirable antihistaminic effects which occur when an antihistamine is the agent used to make the individual drowsy.

Detailed Description of the Invention

The present invention relates to compositions which alleviate pain and induce sleep in an individual. The compositions of the present invention comprise an effective dose of melatonin and an effective dose of one, or more, analgetic agents. The effective doses of melatonin and the analgesic can be combined for administration in a single composition (e.g., a single tablet) or can be administered as individual compositions. The present invention further relates to methods of administering the compositions of the present invention to relieve pain while reducing partially, or totally, sleep disruption.

An art-recognized definition of sleep is the arousable state of unconsciousness. Sleep is also often defined as the state of rest, occurring periodically, characterized by relative physical and nervous inactivity, lessened responsiveness, unconsciousness, and typical brain wave patterns on electroencephalography. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone secreted by the pineal gland in mammals, including humans. Dawson, D. et al . , J. Pineal Res. 15: 112 (1993) . It is believed to have significant hypnotic (sleep inducing) and circadian effects. Melatonin is normally secreted in a circadian (or twenty-four hour) rhythm with plasma levels of approximately 10 pg/ml during the daytime, normally increasing about 10 fold during the nighttime. Waldhauser, F. and Steger, H., PROCEEDINGS OF THE FIRST INTERNATIONAL CONGRESS ON MELATONIN IN HUMANS, pp. 179-191, Vienna, Austria, (Nov.

1985) .

The synthesis and secretion of melatonin is initiated by the onset of darkness through norepinephrine action on the β-adrenoreceptors (and, to a much smaller extent, α-adrenoreceptors) of the pinealocytes. Studies indicate that prostaglandins facilitate this process. Surall, et al . , J. Pharm. Pharmacol . 39:840-843 (1987) ; Murphy, P.J., et al . , Physiol. & Behavior. 55(6) : 1063-1066 (1994) . For example, indomethacin, which inhibits prostaglandin synthesis, greatly impairs the nocturnal increase in melatonin content and partially inhibits melatonin release. Surall, et al . , J. Pharm. Pharmacol . 39:840-843 (1987) . Also, prostaglandin synthesis occurs in areas known to influence sleep and wake activity, especially the preoptic area of the hypothalamus. Murphy, P.J., et al . , Physiol. & Behavior, 55(6) : 1063-1066 (1994) . Prostaglandins appear to act at physiological concentrations in pre- and postsynaptic events at the pineal sympathetic neuro-effector junction. Surall, et al. , J. Pharm. Pharmacol. 39:840-843 (1987) . Exogenous melatonin raises the level of blood plasma melatonin to cause hypnotic effects in individuals. Dawson, D. et al. , J. Pineal Res. 15: 1-12 (1993) . Dollins, et al . Proc. Nat. Acad. Sci.

Non-narcotic analgetic agents, such as aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs

(NSAIDs) , are a heterogeneous group of compounds, often chemically unrelated, that are administered to patients to reduce pain. The non-narcotic analgetic agents encompassed by the present invention include, but are not limited to, salicylates, pyrazolon derivatives, para-aminophenol derivatives, indomethacin, sulindac, tolmetin, propionic acid derivatives, piroxicam, diclofenac, orphenadrine, nabumetone, ketorolac, mefanamic acid, meclofenamate, etodolac, naproxen, ibruprofen, ketoprofen, flurbiprofen, diflunisal and fenoprofen. Other suitable analgetic agents encompassed by this application can be found, for example, in standard pharmacology reference books such as PHYSICIAN' S DESK REFERENCE, 48th Ed., Medical Economics Data Production Company, Montvale, N.J. (1994) ; THE

PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed., eds. Gilman, A.G. et al . , Pergamon Press, Elmsford, N.Y. (1990) .

Analgetic agents can inhibit the production of prostaglandins. THE PHARMACOLOGICAL BASIS OF

THERAPEUTICS. 8th ed. , eds. Gilman, A.G. et al . , Pergamon Press, Elmsford, N.Y. (1990) . Prostaglandins influence pain by sensitizing pain receptors to mechanical and chemical stimulation. Prostaglandins also influence fever, by acting within the hypothalamus to produce the elevation of body temperature. Finally, prostaglandins are involved in inflammation, possibly by inducing vasodilation and increasing vascular permeability. Many analgetic agents, therefore, exhibit antipyretic, and anti-inflammatory qualities. THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 8th ed. , eds. Gilman, A.G. et al. , Pergamon

Press, Elmsford, N.Y. (1990) .

Recent reports have shown that non-narcotic analgetic agents disrupt sleep in animals and humans. Murphy, P.J., et al . , Physiol. & Behavior. 55(6) : 1063-1066 (1994) ; Home, J.A., et al . ,

Electroencephaloαraphv Clin. Neurophvsiol . 49: 409-413

(1980) . For example, acutely administered, low doses of ibuprofen and aspirin altered sleep patterns in healthy, young subjects, and increased the percentage of time spent awake. Murphy, P.J., et al . , Physiol. & Behavior.

55(6) : 1063-1066 (1994) . This is particularly troublesome for individuals who wish to take an analgetic agent for the very purpose of relieving minor pain in order to be able to sleep. One likely reason for this sleep-impairing effect is that administration of an analgetic agent leads to suppression of the normal nocturnal surge in the synthesis of melatonin. For example, when a single dose of aspirin or ibuprofen is administered at 2300 h (11 p.m.) , melatonin synthesis is suppressed by approximately

75k within 75 minutes. Murphy, P.J., et al . , Physiol . & Behavior. 55(6) : 1063-1066 (1994) . Furthermore, analgetic agents which are longer-acting, such as indomethacin, exhibit longer-lasting inhibition of plasma melatonin levels than shorter-acting ones, such as ibuprofen.

Surall, et al . , J. Pharm. Pharmacol . 39:840-843 (1987) . This decrease of melatonin is thought to be due to the analgetic agents' inhibition of prostaglandin synthesis, since prostaglandins play a role in melatonin production. Murphy, P.J., et al . , Phvsiol . & Behavior. 55(6) :

1063-1066 (1994) . The present invention is based on Applicant's discovery that the administration of an effective dose of a non-narcotic analgetic agent and an effective dose of melatonin reduces, partially or totally, the sleep disruption that often accompanies the administration of pain relieving agents. Compositions comprising melatonin and an analgesic, or individual compositions of melatonin and an analgetic agent, utilize the sleep-inducing properties of melatonin and the analgesic properties of analgetic agents to provide pain relief and to induce sleep in an individual experiencing pain.

Pharmaceutical quality melatonin, and melatonin derivatives, are commercially available. As defined herein, an effective dose of melatonin is a dose sufficient to induce sleep in an individual in the presence of an analgetic agent. More specifically, an effective dose of melatonin will generally be less than about 100 mg of melatonin. Preferably, an effective dose will be a single dose of about 0.1 to 10 mg of melatonin, e.g., 1 or 5 mg. In one low dose embodiment of the present invention, the dose of melatonin used is less than about 1 mg, preferably in the range of 0.1 to 0.5 mg, preferably 0.1 to 0.3 mg. In other embodiments, it may be appropriate to use doses between 10 and 100 mg, e.g., 25, 50 or 75 mg.

Non-narcotic analgetic agents are also commercially available. Analgetic agents suitable for use in the present invention include, but are not limited to: aspirin (acetylsalicylic acid) , salicylates other than aspirin, para-aminophenol derivatives (such as acetaminophen -e.g., ANEXSIA^®, BUFFERIN^®, EXCEDRIN^®, LORTAB^®, MIDRIN^®, and TYLENOL^®) , propionic acid derivatives (such as ANAPROX^®, ADVIL^®, IBU^®, LODINE^®, MECLOMEN^®, MOTRIN^®, NALFON^®, NAPROSYN^®, NUPRIN^®, PONSTEL^®, RELAFEN^®, and TORADOL^®) , pyrazolon derivatives, indomethacin, sulindac, tolmetin, piroxicam, diclofenac, orphenadrine nabumetone, ketorolac, mefanamic acid, meclofenamate, etodolac, naproxen, ibruprofen, ketoprofen, flurbiprofen, diflunisal and fenoprofen. (e.g., orphenadrine citrate) . See PHYSICIAN'S DESK REFERENCE. 48th Ed., Medical Economics Data Production

Company, Montvale, N.J. (1994); THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 8th ed. , eds. Gilman, A.G. et al. , Pergamon Press, Elmsford, N.Y. (1990) . Chemical formulations corresponding to the above-described analgetic agents can be found in the USAN AND THE USP

DICTIONARY OF DRUG NAMES, eds. Griffiths, M.C. et al . , United States Pharmacopeial Convention, Inc., Rockville, Md. (1988); THE MERCK INDEX: AN ENCYCLOPEDIA OF CHEMICALS, DRUG NAMES, AND BIOLOGICALS. 11th Ed., eds. Budavari, S. et al . , Merck & Co., Inc., Rahway, N.J.

(1989) , and THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed. , eds. Gilman, A.G. et al . , Pergamon Press, Elmsford, N.Y. (1990) .

As used herein, an effective dose of an analgetic agent is a dose sufficient to relieve pain, i.e., to completely alleviate the sensation of pain or to partially or totally reduce the sensation of pain affecting the individual. Effective doses of analgetic agents are known to those skilled in the art, or are readily ascertained from, for example, Physician's Desk

Reference. PHYSICIAN'S DESK REFERENCE, 48th Ed. , Medical Economics Data Production Company, Montvale, N.J. (1994) . For example, as used in the exemplification, an effective dose of aspirin is 650 mg. A single analgetic agent, or a combination of analgetic agents can be used in the compositions of the present invention. It will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the specific compound being utilized, the particular compositions formulated and the mode of administration.

Dosages for a given recipient will be determined on an individual basis and will be based at least in part on consideration of a recipient's characteristics, such as body size, weight, age and the type and severity of the pain being treated. The compositions of the present invention can optionally include, in addition to the melatonin (or melatonin derivative) and analgetic agent (s) , other components. The components included in a particular composition are determined primarily by the manner in which the composition is administered. For example, a composition to be administered orally in tablet form can include, in addition to melatonin and one or more analgetic agent (s), a filler (e.g., lactose), a binder (e.g., carboxymethylcellulose, gelatin) , a flavoring agent, an adjuvant, a coloring agent, and a coating material (e.g., wax or plasticizer) .

The compositions of the present invention can be employed in admixture with conventional excipients, i.e. , pharmaceutically acceptable organic or inorganic carrier substances, suitable for the route of administration, that do not deleteriously react with the active derivatives. Suitable pharmaceutically-acceptable carriers include, but are not limited to, water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrrolidine. For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.

The present invention also encompasses methods of relieving pain while reducing, totally or partially, sleep disruption (i.e., inducing sleep) . These methods, as described herein, comprise the administration of a composition of the present invention up to 4 hours before an individual desires to fall asleep. As described herein, compositions of the present invention include individual compositions comprising an effective dose of melatonin or an effective dose of an analgetic agent, or a composition comprising an effective dose of more than one analgetic agents. Compositions of the present invention also include compositions combining an effective dose of melatonin and an effective dose of one, or more, analgetic agents. In a preferred embodiment, the compositions will be administered to the individual within a short time period prior to the time the individual desires to fall asleep. For example, in the exemplification, the compositions of melatonin and a composition of an analgesic agent were administered substantially simultaneously approximately 15 minutes prior to the desired sleep time. The administration of the composition can be at four-hour intervals during the period in which the individual desires to be asleep. For example, if the individual awakens during the night and desires to go back to sleep, the individual can take (e.g., self administration or administered by another individual) an additional dose of a composition. Subsequently doses of the composition can be administered, as needed, such as at 4 hour intervals. To produce the desired effect of pain relief and sleep inducement, the effective doses of melatonin and analgetic agent (s) can be administered simultaneously or substantially simultaneously, i.e., up to within 6-8 hours of each other. This is because at the effective dosage range of melatonin, e.g., 0.1 mg. to 10.0 g., elevated plasma melatonin levels may last for eight hours. Furthermore, some analgetic agents have sufficiently long half-lives for such administration to be effective. In a preferred embodiment of this invention, the method of administration is oral administration (ingestion) or transdermal administration. However, the compositions can be administered in a number of ways known to those of skill in the art, including, but not limited to: nasal administration, intraocular administration, administration by suppository, or by injection.

The form in which the composition can be administered (for example, tablet, capsule, bolus, powder, solution, nasal spray, eye drop or gel) will depend on the route by which it is administered. Compositions of the present invention can also be administered through the use of time release capsule (s) , a percutaneous patch or a microsmatic pump.

The compositions of the present invention can be administered whenever an individual experiences pain, for example, after surgery, injury, influenza or other illness causing muscle or joint pains, strenuous physical labor or exercise, or upon onset of tension or migraine headaches or menstrual cramps .

Thus, as a result of Applicant's discovery, compositions of melatonin and one or more analgetic agents, and methods of their use are now available for the treatment of pain and the inducement of sleep. The use of melatonin which produces endogenous blood melatonin levels sufficient to induce sleep has a number of advantages over conventional chemical hypnotics, such as benzodiazepines . Benzodiazepines are often the drugs of choice for the treatment of insomnia. However, they alter the composition of electroencephalogram (EEG) sleep architecture and endogenous circadian rhythmicity. THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed., eds. Gilman, A.G. et al . , Pergamon Press, Elmsford, N.Y. (1990) . In normal individuals, sleep consists of a series of stages which have a precise temporal organization. Benzodiazepines can alter the composition and lengths of these stages, and chronic use of such drugs can give rise to harmful cumulative effects, giving rise to nightmares, anxiety, irritability, and tachycardia. Use of benzodiazepines in combination with analgesics may be especially troublesome, since some analgesics, such as aspirin, have also been shown to have a significantly disruptive effect on sleep architecture. Home, J.A. , et al . , Electroencephalocrraphy Clin. Neurophysiol . 49: 409-413 (1980) .

Melatonin does not affect sleep architecture as determined by EEG in normal, healthy patients. Dawson, D. et al . , J. Pineal Res. 15: 1-12 (1993) . Furthermore, inducing sleep using melatonin does not produce adverse residual effects the day following administration, as do conventional sleep-inducing drugs. Melatonin is naturally metabolized within hours of administration. Thus, although the sleep-inducing effect of low doses of melatonin is fast-acting, it is not long-lasting (i.e., the blood levels of melatonin would not remain at nocturnal levels beyond the usual desired period of sleep) . Therefore, blood melatonin levels fall back to within normal daytime levels after approximately seven hours and an individual would awake, for example, the next day, with blood melatonin levels at the normal daytime levels, without any feelings of sleepiness.

Use of melatonin is also unlikely to have the dangers of drug abuse and/or overdose, which are present with conventional chemical hypnotics. Moreover, because melatonin is a naturally-occurring, endogenous substance, the doses of melatonin described herein would reasonably lack the potential amnesia-inducing effects of the benzodiazepines. THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 8th ed., eds. Gilman, A.G. et al . , Pergamon Press, Elmsford, N.Y. (1990) . Finally, benzodiazepines have actually been demonstrated to suppress endogenous melatonin production. Dawson, D. et al. , J. Pineal Res. 15: 1-12 (1993) .

The present invention is further illustrated by the following Exemplification, which is not intended to be limiting in any way.

Exemplification: Patient Selection and Protocol

One healthy male subject participated in the study. He experienced chronic mild muscular pain caused by physical exertion. On the first night of the experiment he orally administered to himself melatonin alone (0.3 mg) at 2200 h. On the second night of the experiment he orally administered to himself aspirin alone (650 mg) at 1900 h, and again at 2200 h. On the third night of the experiment he orally administered to himself a combination of melatonin (0.3 mg) and aspirin (650 mg) at 2200 h. He recorded his subjective impressions regarding the relative ease with which sleep was induced after the administration of each substance. Sleep induction was measured by having the subject look at a clock every few minutes and make a note of the time, until he fell asleep. Sleep onset occurred within approximately fifteen to twenty minutes of administration of either melatonin or aspirin alone. However, it occurred within approximately three minutes of administration of the combination of melatonin and aspirin

Thus, it was found that the melatonin alone failed to induce sleep because of the continuing perception of pain. The aspirin relieved the pain, but also failed to induce sleep. However, the combination of melatonin and aspirin used was highly effective in inducing sleep.

Equivalents

Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed within the scope of this invention.

Claims

CLAIMSWhat is claimed is:

1. A composition which relieves pain and induces sleep when administered to an individual desiring sleep and seeking relief from pain, comprising an effective dose of melatonin and an effective dose of one or more non-narcotic analgetic agents.

2. The composition of Claim 1 wherein the dose of melatonin is less than 100 mg.

3. The composition of Claim 2 wherein the dose of melatonin is between 0.1 and 10.0 mg.

4. The composition of Claim 3 wherein the dose of melatonin is 0.3 mg.

5. The composition of Claim 1 wherein the one or more analgetic agents is selected from the group consisting of: salicylates, pyrazolon derivatives, para-aminophenol derivatives, indomethacin, sulindac, tolmetin, propionic acid derivatives, piroxicam, diclofenac, orphenadrine, nabumetone, ketorolac, mefanamic acid, meclofenamate, etodolac, naproxen, ibruprofen, ketoprofen, flurbiprofen, diflunisal and fenoprofen.

6. A composition which relieves pain and induces sleep when administered to an individual, comprising a 0.3 mg of melatonin and 650 mg of aspirin.

7. A method of relieving pain and inducing sleep, comprising administering to an individual desiring sleep and seeking relief from pain an effective dose of melatonin and an effective dose of one or more analgetic agents.

8. The method of Claim 7 wherein the dose of melatonin is less than 100 mg.

9. The method of Claim 7 wherein the dose of melatonin is between 0.1 and 10.0 mg.

10. The method of Claim 6 wherein the dose of melatonin is between 0.1 and 0.3 mg.

11. The method of Claim 7 wherein the dose of melatonin is 0.3 mg.

12. The method of Claim 7 wherein the one or more analgetic agents is selected from the group consisting of: salicylates, pyrazolon derivatives, para-aminophenol derivatives, indomethacin, sulindac, tolmetin, propionic acid derivatives, piroxicam, diclofenac, orphenadrine, nabumetone, ketorolac, mefanamic acid, meclofenamate, etodolac, naproxen, ibruprofen, ketoprofen, flurbiprofen, diflunisal and fenoprofen.

13. The method of Claim 7 wherein the effective dose of melatonin and the effective dose of one or more analgetic agents are administered in a single composition.

14. The method of Claim 13 wherein the composition is administered orally.

15. The method of Claim 7 wherein the effective dose of melatonin and the effective dose of one or more analgetic agents are administered orally.

16. The method of Claim 7 wherein the effective dose of melatonin and the effective dose of one or more analgetic agents are administered transdermally.

17. The method of Claim 7 wherein the compositions are administered up to 4 hours before the individual desires to fall asleep.

18. The method of Claim 7 wherein the compositions are administered at four-hour intervals.

19. The method of Claim 7 wherein an additional effective dose of melatonin is administered subsequent to the initial administration of melatonin.