The present invention relates to methods for the treatment of pain. More particularly, the invention relates to the use of certain branched-chain fatty acids (BFAs) and derivatives thereof in the treatment of pain in mammals and in particular in humans.
Pain is a complex sensation and is the most common symptom of disease. Pain which is classified as somatogenic may be nociceptive pain which is due to a noxious stimulus (chemical, thermal, mechanical etc.) that activates pain receptors , or neuropathic pain which results from dysfunction of the central or peripheral nervous system and is often poorly localized.
Pain may also be classified as being acute or chronic in nature. Acute pain is usually a result of injury (e.g. trauma or disease), it lasts a short time and is typically resolves as the injured tissue heals or soon after. Chronic pain is usually defined broadly and arbitrarily as a pain persisting for over one month beyond the resolution of an acute tissue injury, pain persisting or recurring for more than 3 months, or pain associated with tissue injury that is continued or progressed [The Merck Manual, 1999].
Several pain syndromes are difficult to classify according to these criteria. These include, for example, chronic headache and continuous acute pain produced by the invasion of body tissues in malignant diseases.
Neuropathic pain is a common type of pain which can develop after injury to the nervous system and is usually a chronic pain. Neuropathic pain may result by trauma, central nervous system (CNS) pathology (e.g. stroke, spinal cord injury), by diseases such as diabetes, herpes zoster, or late stage of cancer, or by chemical injury. It may also develop after amputation.
The long-lasting neural mechanisms associated with chronic pain differ from those observed in acute pain [Loeser and Melzack (1999) Lancet 353: 1607-9]. Accordingly, also the pharmaceutical agents used to treat the various pain syndromes are different. It is well known that drugs that are useful against acute pain may be ineffective against chronic pain and drugs active, for example, against neuropathic pain may not be effective analgesics in other kinds of pain.
A variety of analgesic agents have been demonstrated as useful in the treatment of pain symptoms. Yet so far, the majority of available analgesics possess undesirable side effects.
Opioids are substances that act as agonists of opioid receptors in the CNS, and are considered as the most potent analgesic agents. Agents such as morphine and related opioid compounds, are often required for relief of severe pain. However, these narcotic drugs have the severe drawback of leading to dependence and addiction. In addition, patients treated with opioids tend to develop tolerance to the drug, which leads to increasing dosage of the drug needed for exerting the analgesic effect and to subsequent withdrawal symptoms. Further side effects associated with opioid drugs include nausea, sedation and respiratory depression.
Nonopioid analgesics, e.g. cyclooxygenase inhibitors such as acetaminophen (=paracetamol) and nonsteroidal anti-inflammatory drugs (NSAIDs) are often effective for treatment of mild to moderate pain. Anti-inflammatory agents of the NSAID class such as acetylsalicylic acid (aspirin), indomethacin, diclofenac and benzydamine have been used as analgesics in pain associated with trauma and inflammation. Nevertheless, clinical trials are still inconclusive. Common side effects of the NSAID class of drugs include: gastrointestinal irritation and ulceration, blockade of platelet aggregation, renal dysfunction and hepatic damage.
Another major class of analgesics is the local anaesthetics that block sodium channels. Compounds of this class, e.g. lidocaine, when topically applied to the spine, have been found effective for control of pain after surgery or trauma, but require expertise and infrastructure to administer and monitor properly. Systemic infusion of lidocaine can reduce acute pain, but requires continuous monitoring so that resuscitation from seizures or apnea can be performed immediately.
N-methyl-D-aspartate (NMDA) receptor antagonists are useful in treating neuropathic pain. It has been found that several sites on the NMDA receptor complex, activated by the excitatory amino acid glutamate, are analgesic targets. For example, Ketamine, which blocks the open calcium channel within this complex, has been suggested for use preoperatively or in neuropathic pain. Clinical studies confirm ketamine""s merit as an analgesic or co-analgesic (e.g. with morphine). Nevertheless, psychotomimetic and other side effects such as salivation or cardiac stimulation restrict the applicability of standard doses of ketamine [Martindale: The Extra Pharmacopeia. 31st Edition. London: Pharmaceutical Press, (Editor Reynolds) 1996, pg. 1258-9].
Antidepressants, e.g. the tricyclic antidepressants amitriptyline and imipramine, and the serotonin re-uptake inhibitor paroxetine, have also been proven beneficial as analgesics. Tricyclic antidepressants can be helpful in several chronic pain states, especially in patients with head pain (including headache), central pain, and neuropathic pain. However, these drugs have the potential for adverse side effects, including anticholinergic effects and life-threatening cardiovascular effects.
Anticonvulsants have also been found to have useful analgesic effects. Gabapentin, has shown promise for the treatment of chronic pain [Rowbotham et al. (1998) JAMA 280: 1837-42] and carbamazepine and phenytoin, can be effective in the treatment of a range of neuropathic pain states. In particular, it has been found that trigeminal neuralgia responds well to carbamazepine [Green and Selman (1991) Headache 31: 588-592]. Sodium valproate has been reported as being effective in the prophylactic treatment of migraine [Hering and Kuritzky (1992) Cephalalgia 12: 81-84]. However, sodium valproate was found ineffective in the placebo controlled study in treating postoperative pain, which is an acute pain [Martin et al. (1988) Ann FrAnesth Reanim 7:387-92]. Some analogs of valproic acid that have been tested as potential anticonvulsant drugs were found sedative or had toxic effects [Keane et al. (1983) Neuropharmacology 22: 875-879].
Serious side effects that have been reported with anticonvulsant drugs, including deaths from hematological reactions, impaired mental and motor function, may limit clinical use, particularly in elderly people [Martindale: The Extra Pharmacopeia. 31st Edition. London: Pharmaceutical Press, (Editor Reynolds) 1996, pgs. 367-381]. Moreover, the results of several clinical trials with anticonvulsant drugs were disappointing and show conflicting results [McQuay et al. (1995) BMJ 311:1047-1052]. In particular, there is no evidence that anticonvulsants are effective for acute pain [Wiffen et al. (2000) The Cochrane Library, Issue 4, Oxford: Update Software].
Overall, it seems that the therapeutic effects of many of the existing analgesic agents are controversial and often inadequate. In addition, most of the currently available analgesic medicaments suffer from serious drawbacks which limit their use.
Clearly, there is an unmet clinical need for novel substances for effective treatment of various forms of pain, including acute and neuropathic pain.
The aim of the present invention is to provide methods for the treatment and/or prophylaxis of pain in mammals, in particular acute and neuropathic pain in humans.
Thus the present invention relates, in one aspect, to methods of treating or alleviating pain in mammals, comprising administering to a mammal suffering from pain, a pain-alleviating amount of a compound of the general formula (I) or (II) or pharmaceutically acceptable salts thereof.
The useful compounds according to the invention are of the general formula (I): 
and pharmaceutically acceptable salts thereof, wherein:
R1 is a saturated or unsaturated chain of 1-18 carbons in length; and
R2 is a saturated or unsaturated chain of 1-18 carbons in length, with the proviso that R1 and R2 are not both propyl;
and compounds of the general formula (II): 
and pharmaceutically acceptable salts thereof, wherein:
R1 is a saturated or unsaturated chain of 1-18 carbons in length; and
R2 is a saturated or unsaturated chain of 1-18 carbons in length; and
A is selected from the group consisting of COOL and CONRxe2x80x2-Rxe2x80x3, wherein L is a lipid moiety selected from the group consisting of glycerol, C3-20 fatty acid monoglycerides, C3-20 fatty acid diglycerides, hydroxy-C2-6-alkyl esters of C3-20 fatty acids, hydroxy-C2-6-alkyl esters of lysophosphatidic acids, lyso plasmalogens, lysophospholipids, lysophophatidic acid amides, glycerophosphoric acids, sphingolipids, lysophosphatidylethanolamine, and N-mono-(C1-4)alkyl and N,N-di-(C1-4)alkyl and quaternary derivatives of said lysophosphatidylethanolamine; and Rxe2x80x2 and Rxe2x80x3 are each independently selected from the group consisting of hydrogen and a lower alkyl group comprising 1-5 carbon atoms.
The methods encompassed by the invention, include methods for treatment and/or prophylaxis of pain in mammals, and in particular in humans. Said pain may be acute, chronic or neuropathic pain.
According to one preferred embodiment, the acute pain is selected from, but not limited to, post-operative pain, labor pain, toothache, pain induced by bums, muscle pain and pain accompanying myocardial infarction.
According to another preferred embodiment of the invention, the neuropathic pain is selected from, but not limited to, post-herpetic neuralgia, diabetic neuropathy, and trigeminal neuralgia.
According to yet another preferred embodiment, the treated pain is associated with a pathological condition or disease state which may be selected from, but not being limited to, the group consisting of stroke, spinal cord injury, inflammation condition, cancer, trigeminal neuralgia, arthritis, sickle cell disease, hemophilia, diabetes, herpes zoster and headache including cluster headache.
In currently preferred embodiments, the useful compounds are selected from the group consisting of:
2-Pentylheptanoic acid [M (5,5)],
2-Propyldodecanoic acid [M (3,10)],
2-Propylnonanoic acid [M (3,7)],
2-Heptylnonanoic acid [M (7,7)],
1-stearoyl-2-propylnonanoyl-sn-glycero-3-phosphocholine,
1-stearoyl-2-pentylheptanoyl-sn-glycero-3-phosphocholine,
1-stearoyl-2-heptylnonanoyl-sn-glycero-3-phosphocholine, and
1-stearoyl-2-propyldodecanoyl-sn-glycero-3-phosphocholine.
In another aspect, the present invention relates to compounds of the formula 
wherein:
R1 is a saturated or unsaturated chain of 6-18 carbons in length; and
R2 is a saturated or unsaturated chain of 1-18 carbons in length; and
A is selected from the group consisting of COOL and CONRxe2x80x2-Rxe2x80x3, wherein L is a lipid moiety selected from the group consisting of glycerol, C3-20 fatty acid monoglycerides, C3-20 fatty acid diglycerides, hydroxy-C2-6-alkyl esters of C3-20 fatty acids, hydroxy-C2-6-alkyl esters of lysophosphatidic acids, lyso plasmalogens, lysophospholipids, lysophophatidic acid amides, glycerophosphoric acids, sphingolipids, lysophosphatidylethanolamine, and N-mono-(C1-4)alkyl and N,N-di-(C1-4)alkyl and quaternary derivatives of said lysophosphatidylethanolamine; and Rxe2x80x2 and Rxe2x80x3 are each independently selected from the group consisting of hydrogen and a lower alkyl group comprising 1-5 carbon atoms; and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compounds of the invention are those including a lipid moiety at position A. More preferably the lipid moiety is a phospholipid. Currently most preferred compounds include a branched-chain derivative having a lyso-phosphatidylcholine moiety at position A.
In still another aspect, the present invention relates to pharmaceutical compositions for treating pain, comprising a pain-alleviating amount of a compound of the formula mentioned above and at least one pharmaceutically acceptable carrier.
Further objects of the present invention will become apparent to those skilled in the art upon further review of the following disclosure, including the detailed descriptions of specific embodiments of the invention.