Wednesday, May 13, 2009

Can Post-Herpetic Neuralgia be connected to a badly broken wisdom tooth?

I have a very badly broken wisdom tooth. The last week it has been excruiatingly painful, and now think me taking too many painkillers to numb pain.


(Am going to dentist on monday so hopefully sorted out)





Is this just the tooth giving me hell or could it be Post-herpetic Neuralgia?

Can Post-Herpetic Neuralgia be connected to a badly broken wisdom tooth?
Pain is an unpleasant sensation that occurs as a result of injury to the body or as a manifestation of a diseased state. Pain can be classified in many ways. For example, pain can be classified based on its duration (acute or chronic pain) and by the underlying cause (nociceptive or neuropathic).





[0004] Nociceptive pain results directly from local tissue injury whereas neuropathic pain follows nerve injury. Key features of nociceptive pain are that it can be experienced as sharp, dull, or aching, and that there may be radiation of the pain, or the perception of pain in a different area than where the nerves are being stimulated. For example, when a person experiences a heart attack, pain may radiate from the chest down the arms or up the neck, even though there is no tissue damage in these areas. Examples of nociceptive pain include pain from surgical incisions, bone pain from fractures or metastatic cancer, and pain from joint diseases such as osteoarthritis and rheumatoid arthritis.





[0005] Neuropathic pain occurs as a result of damage to, or dysfunction, of the nervous system. Neuropathic pain is frequently described as burning, tingling or having an electrical shock-like feeling. Another key feature of this type of pain is its paradoxical occurrence upon stimulation that otherwise would not be expected to cause pain. For example, a condition called trigeminal neuralgia may cause patients to feel extreme pain upon a light touch on the cheek. Examples of neuropathic pain include the pain resulting from diabetes and HIV infection, and postherpetic neuralgia, commonly called zoster, which is a painful condition caused by the chicken pox virus long after the initial infection has healed, in many cases years later. Neuropathic pain frequently coexists or follows nociceptive pain, as for example when a patient that has had a surgical procedure continues to experience pain long after the wound has healed.





[0006] Pain is a worldwide problem with serious health and economic consequences. The medical effort to treat pain, known as pain management, addresses a large and under-served market. According to IMS Health, the worldwide prescription market for pain drugs totaled over $23 billion in 2003, of which nearly $18 billion was spent in the United States. For example, in the United States medical economists estimate that pain results in approximately $100 billion of costs annually, as reported by the National Institutes of Health (NIH). Pain in the hospital is associated with increased length of stay, longer recovery times and poorer patient outcomes, all of which have health care quality and cost implications. Approximately 40 million Americans are unable to find relief from their pain, according to the NIH and more than 30 million Americans suffer chronic pain for which they visit a doctor.





[0007] Drugs are the principal means of treating pain. The pain management market is anticipated to grow at a compounded annual growth rate of 10% through 2010 due to a number of factors, including a rapidly aging population with an increasing need and desire to address pain-related ailments; longer survival times for patients with painful chronic conditions, such as cancer and AIDS; patients' increased demand for effective pain relief; and increasing recognition of the therapeutic and economic benefits of effective pain management by physicians, health care providers and payers.





[0008] Drugs that treat pain are referred to as analgesics. The type of analgesic selected for treatment depends upon the severity of the pain. For mild pain, the type of pain associated with many headaches or joint pain, weak analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and Celebrex.RTM. (Pfizer) are used. For moderate pain, the type of pain associated with wisdom tooth extraction, other minor surgery and some arthritis pain, NSAIDs, weak opioids such as codeine or short-acting formulations of strong opioids such as Percocet.RTM. (Endo) may be used. Severe pain, which may occur following major surgery, advanced arthritis or cancer, requires strong opioids such as morphine, oxycodone, hydrocodone or fentanyl.





[0009] Despite widespread clinical use of drugs for pain, pain management remains less than optimal due to a variety of factors including: i) insufficient efficacy (NSAIDs are effective in treating only minor pain. Narcotics, the current standard of care for severe nociceptive pain, reduce pain less than 50% in most situations. Neuropathic pain is poorly treated by all existing analgesics); ii) side effects (NSAIDs often cause gastrointestinal ulcers, and more than 20,000 patients die each year from gastrointestinal bleeding induced by NSAIDs. One of the COX 2-selective NSAIDs, Vioxx.RTM. (Merck), has been shown to cause increased risk of heart attacks and possibly stroke. Use of narcotics is associated with nausea and vomiting in most patients. High-dose narcotics cause sedation and may also cause respiratory depression, or a decreased ability to breathe spontaneously. Narcotics used chronically can cause severe constipation that leads many patients to stop using them, and narcotics may sometimes cause severe itching. All of the drugs used to treat neuropathic pain frequently cause problems with coordination and sedation); iii) frequent dosing (Drugs used to treat neuropathic pain require frequent dosing that makes their use inconvenient, often leading to reduced patient compliance); iv) physical dependence (Narcotics, when used chronically, can cause physical dependence. Fear of physical dependence often influences clinicians to prescribe less than adequate doses of narcotic analgesics. Similar fears lead many patients to refuse narcotic analgesics); and v) diversion potential (Narcotics are often used by drug abusers, leading to considerable potential for diversion of legitimate narcotic analgesics for illicit uses. In fact, many pharmacies have removed high-dose narcotic analgesics from their inventories because of the risk of theft).





[0010] Pain management is of particular importance for treating severe post-surgical pain. There are over three million surgeries performed in the United States each year that result in severe post-surgical pain. Morphine and related narcotics, which are presently the standard of care for acute post-surgical pain, have serious side effects including respiratory depression, nausea, itching and sedation. In addition, many currently marketed drugs that treat pain require frequent dosing, which makes usage less convenient for patients.





[0011] As a result of the shortcomings of existing drugs that treat pain, capsaicin has become a front-runner of research and development for it use in treating pain.





[0012] Capsaicin, a pungent substance derived from the plants of the solanaceae family (hot chili peppers) has long been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers C-fibers and A-delta fibers that are believed to signal pain. From studies in animals, capsaicin appears to trigger C-fiber membrane depolarization by opening cation channels permeable to calcium and sodium. Recently one of the receptors for capsaicin effects has been cloned. Capsaicin can be readily obtained by ethanol extraction of the fruit of capsicum frutescens or capsicum annum. Capsaicin is known by the chemical name N-(4-hydroxy-3-methoxybenzyl)-8-methylno... Capsaicin is practically insoluble in water, but freely soluble in alcohol, ether, benzene and chloroform. Therapeutically capsaicin has been used as a topical analgesic. Capsaicin is available commercially as Capsaicin USP from Steve Weiss %26amp; Co., 315 East 68.sup.th Street, New York, N.Y. 10021 and can also be prepared synthetically by published methods. See Michalska et al., "Synthesis and Local Anesthetic Properties of N-substituted 3,4-Dimethoxyphenethylamine Derivatives", Diss Pharm. Pharmacol., Vol. 24, (1972), pp. 17-25, (Chem. Abs. 77: 19271a), discloses N-pentyl and N-hexyl 3,4-dimethoxyphenylacetamides which are reduced to the respective secondary amines.





[0013] Capsaicin is listed in the pharmacopoeias of the United Kingdom, Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan, Poland, Portugal, Spain, and Switzerland and has previously been listed in the United States Pharmacopoeia and the National Formulary. The FDA proposed monographs on analgesic drug products for over-the-counter (OTC) human use. These include capsaicin and capsicum preparations that are regarded as safe and effective for use as OTC external analgesics. Capsaicin is the only chemical entity of Capsicum recognized by the FDA. Capsaicin (USP) contains not less than 110% total capsaicinoids which typically corresponds to 63% pure capsaicin. USP capsaicin is trans-capsaicin (55-60%) and also contains the precursors dihydrocapsaicin and nordihydrocapsaicin.





[0014] Capsaicin mediated effects include: (i) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive A-delta and C-fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of nociceptive fibers without affecting the number of non-nociceptive fibers.





[0015] Capsaicin works to relieve pain by causing a localized degradation of the C neuron endings, and it is the only analgesic known to relieve pain by this mechanism. The activity of capsaicin results from its binding to, and activating, an ion channel called vanilloid receptor 1, or VR1. Under normal circumstances, when the VR1 ion channel is activated it opens for a short time, causing the C neurons to transmit a pain signal toward the brain. When capsaicin binds to, and activates VR1, it causes a series of events within the cell that degrade the pain-sensing endings, or terminals of the C neuron, thereby preventing the neuron from transmitting pain signals.





[0016] The effects of capsaicin are confined exclusively to the region of application because of low distribution to other areas of the body after capsaicin is administered. For example, after injection into a joint space or after application in a surgical procedure to the cut surfaces of skin, muscle and bone, capsaicin enters the blood slowly by diffusion from its site of initial application. Thereafter, capsaicin is highly metabolized, or broken down, by the liver into various inactive compounds, none of which retain any of the analgesic properties of capsaicin. As a consequence, capsaicin does not usually act at sites in the body distant from its initial application, nor is the body exposed to any derivatives of capsaicin that could act in a similar manner. By contrast, opioids and many other analgesics must be given by mouth or by intravenous injection, thereby subjecting the patient to circulation of high concentrations of drug. These high circulating concentrations may exert undesirable side effects by acting on parts of the body unrelated to pain perception. For example, opioids may cause constipation when used chronically. Opioids also may cause alteration of mood, and alertness, and can cause patients to feel drowsy, euphoric, or sleepy. These effects, when experienced by patients in the hospital, tend to increase rehabilitation time because patients are often sedated and therefore unable to begin the recovery process.





[0017] Humans have long been exposed to dietary sources of capsaicin-containing spices and to topical preparations used for a variety of medical indications. This vast experience has not revealed significant or lasting adverse effects of capsaicin exposure. The recent determination of potential therapeutic effects of capsaicin on unmyelinated sensory afferent nerve fibers require diligent consideration of this compound for further pharmaceutical development.





[0018] Because of the ability of capsaicin to desensitize nociceptors in peripheral tissues, its potential analgesic effects have also been assessed in various clinical trials. However, since the application of capsaicin itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated, patient compliance has been poor and the drop out rates during clinical trials have exceeded fifty percent. The spontaneous burning pain and hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of capsaicin application. This activation and sensitization occur prior to the desensitization phase. The activation phase could be a barrier to use of capsaicin because of the pain produced.





[0019] Prior publications describe topical administration of capsaicin for the treatment of various conditions. For example, U.S. Pat. No. 4,997,853 (Bernstein) describes methods and compositions utilizing capsaicin as an external analgesic. U.S. Pat. No. 5,063,060 (Bernstein) describes compositions and methods for treating painful, inflammatory or allergic disorders. U.S. Pat. No. 5,178,879 (Adekunle, et al.) describes methods for preparing a non-greasy capsaicin gel for topical administration for the treatment of pain. U.S. Pat. No. 5,296,225 (Adekunle, et al.) describes indirect methods of treating orofacial pain with topical capsaicin. U.S. Pat. No. 5,665,378 (Davis, et al.) describes transdermal therapeutic formulations comprising capsaicin, a nonsteroidal anti-inflammatory agent and pamabrom for the treatment of pain. U.S. Pat. No. 6,248,788 (Robbins, et al.) describes administration of 7.5% capsaicin cream in combination with marcaine epidural injections in patients suffering from long-term persistent foot pain. U.S. Pat. No. 6,239,180 (Robbins) describes combining capsaicin loaded patches with local anesthesia to treat peripheral neuropathy. The use of topical capsaicin has also been described in the art to treat conditions as diverse as post mastectomy pain syndrome (Watson and Evans, Pain 51: 375-79 (1992)); painful diabetic neuropathy (Tandan et al., Diabetes Care 15: 8-13 (1992)); The Capsaicin Study Group, Arch Intern Med 151: 2225-9 (1991); post-herpetic neuralgia (Watson et al., Pain 33: 333-40 (1988)), Watson et al., Clin. Ther. 15: 510-26 (1993); Bernstein et al., J. Am Acad Dermatol 21: 265-70 (1989) and pain in Guillian-Barre syndrome (Morganlander et al., Annals of Neurology 29:199 (1990)). Capsaicin has also been used in the treatment of osteoarthritis (Deal et al., Clin Ther 13: 383-95 (1991); McCarthy and McCarthy, J. Rheumatol 19: 604-7 (1992); Altman et al., Seminars in Arthritis and Rheumatism 23: 25-33 (1994).





[0020] Capsaicin is currently marketed for topical administration in the form of over-the-counter, low dose, non-sterile creams and patches, which tend to be poorly absorbed. There are more than thirty brands of creams and patches, including Capzasin-P.RTM. (Chattem) and Zostrix.RTM. (Rodlen Laboratories). These formulations are generally crude preparations of capsaicin that may contain other chemical entities. These over-the-counter preparations can be purchased widely without a prescription and are used topically by consumers to relieve pain in conditions such as osteoarthritis, shingles (herpes zoster), psoriasis and diabetic neuropathy.





[0021] It would therefore be advantageous to provide a topical capsaicinoid gel formulation and methods of use thereof that would be useful in different clinical settings as compared with current over-the-counter and prescription products. Specifically, it would be advantageous to provide a topical capsaicinoid gel formulation for use by physicians in the surgical setting prior to wound closure, e.g., in bunion removal surgery, hernia repair and other surgeries, by orthopedic surgeons and other physicians for the treatment of osteoarthritic knee joint disease and tendonitis, and for certain forms of localized neuropathic pain that are not amenable to treatment with currently marketed topical preparations.



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