Doxepin chemical structure
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Doxepin

Doxepin is a tricyclic antidepressant, known under many brand-names such as Aponal®, the original preparation by Boehringer-Ingelheim, now part of the Roche group; Adapine®, Sinquan® and Sinequan® (Pfizer Inc.); and Zonalon®, a cream-based preparation. more...

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Pharmacology

Doxepin inhibits the reuptake of serotonin and noradrenaline from the synaptic cleft (dual action). The reuptake-inhibition of dopamine is very weak.

It has antagonistic effects (blockade) on a variety of postsynaptic receptors:

  • Extremely strong : H1, H2
  • Strong : 5-HT2, Alpha1, Muscarinic
  • Moderate : 5-HT1
  • Weak : D2, Alpha2

These effects account for the actions as well for most side-effects (sedation, hypotension, anticholinergic side-effects, massive weight gain). Doxepin shows strong antagonism against the effects of Reserpin (amine depletion) in the animal model. Like other 'classical' antidepressants it has a sodium channel blocking activity, possibly accounting for its analgesic action. Additionally, Doxepin exerts a strong local-anesthetic action.

Peak plasma levels are seen 2 to 3 hours after oral dosing.

Toxicology

acute toxicity:

  • Mouse : i.v. 15 - 20mg/kg body weight, oral 148 - 178mg/kg body weight
  • Rat : i.v. 13 - 19mg/kg body weight, oral 346 - 460mg/kg body weight
  • Human : Not exactly known, clinical experience indicates a rather high acute toxicity, as is the case with other tri-/tetracyclics. Fatal dose in sensitive adults may be as low as 500 to 1,000mg oral (7 to 14mg/kg). In children below 12 yrs. of age any oral intake is to be considered as serious.

chronic toxicity

  • Dog and Rat : Fat deposits in liver cells and decrease of triglyceride levels in plasma
  • Human : Data not available

Indications

Approved uses may vary by country. In the United States, the only FDA approved use of doxepin is the treatment of depression. All other uses should be considered off-label.

  • Depression
  • Anxiety disorder, longterm-treatment is possible
  • Insomnia, also suitable for longterm-treatment
  • Alleviation of the symptoms of alcohol and drug withdrawal (N.B.: Doxepin does not suppress seizure activity in alcoholics ('rum fits'). Cotreatment with benzodiazepines or barbiturates is needed to treat seizures effectively.)
  • Gastrointestinal ulceration and other GI-problems (e.g. irritable bowel syndrome), whether part of depression or not. The action is due to strong H2-receptor antagonism. The efficiacy is comparable to H2-Receptor-Inhibitors.
  • Chronic pain, particular tension headaches, whether associated with depression or not
  • External treatment of itching skin disease with Zonalon®

Contraindications

absolute :

  • known hypersensitivity to doxepin or other dibenzoxepines or other ingredients of the drug
  • acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
  • acute delirium tremens
  • untreated closed angle glaucoma
  • hypertrophy of the prostate with urine retention
  • paralytic ileus

relative :

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Pain
From Gale Encyclopedia of Medicine, 4/6/01 by Julia Barrett

Definition

Pain is an unpleasant feeling that is conveyed to the brain by sensory neurons. The discomfort signals actual or potential injury to the body. However, pain is more than a sensation, or the physical awareness of pain; it also includes perception, the subjective interpretation of the discomfort. Perception gives information on the pain's location, intensity, and something about its nature. The various conscious and unconscious responses to both sensation and perception, including the emotional response, add further definition to the overall concept of pain.

Description

Pain arises from any number of situations. Injury is a major cause, but pain may also arise from an illness. It may accompany a psychological condition, such as depression, or may even occur in the absence of a recognizable trigger.

Acute pain

Acute pain often results from tissue damage, such as a skin burn or broken bone. Acute pain can also be associated with headaches or muscle cramps. This type of pain usually goes away as the injury heals or the cause of the pain (stimulus) is removed.

To understand acute pain, it is necessary to understand the nerves that support it. Nerve cells, or neurons, perform many functions in the body. Although their general purpose, providing an interface between the brain and the body, remains constant, their capabilities vary widely. Certain types of neurons are capable of transmitting a pain signal to the brain.

As a group, these pain-sensing neurons are called nociceptors, and virtually every surface and organ of the body is wired with them. The central part of these cells is located in the spine, and they send threadlike projections to every part of the body. Nociceptors are classified according to the stimulus that prompts them to transmit a pain signal. Thermoreceptive nociceptors are stimulated by temperatures that are potentially tissue damaging. Mechanoreceptive nociceptors respond to a pressure stimulus that may cause injury. Polymodal nociceptors are the most sensitive and can respond to temperature and pressure. Polymodal nociceptors also respond to chemicals released by the cells in the area from which the pain originates.

Nerve cell endings, or receptors, are at the front end of pain sensation. A stimulus at this part of the nociceptor unleashes a cascade of neurotransmitters (chemicals that transmit information within the nervous system) in the spine. Each neurotransmitter has a purpose. For example, substance P relays the pain message to nerves leading to the spinal cord and brain. These neurotransmitters may also stimulate nerves leading back to the site of the injury. This response prompts cells in the injured area to release chemicals that not only trigger an immune response, but also influence the intensity and duration of the pain.

Chronic and abnormal pain

Chronic pain refers to pain that persists after an injury heals, cancer pain, pain related to a persistent or degenerative disease, and long-term pain from an unidentifiable cause. It is estimated that one in three people in the United States will experience chronic pain at some point in their lives. Of these people, approximately 50 million are either partially or completely disabled.

Chronic pain may be caused by the body's response to acute pain. In the presence of continued stimulation of nociceptors, changes occur within the nervous system. Changes at the molecular level are dramatic and may include alterations in genetic transcription of neurotransmitters and receptors. These changes may also occur in the absence of an identifiable cause; one of the frustrating aspects of chronic pain is that the stimulus may be unknown. For example, the stimulus cannot be identified in as many as 85% of individuals suffering lower back pain.

Other types of abnormal pain include allodynia, hyperalgesia, and phantom limb pain. These types of pain often arise from some damage to the nervous system (neuropathic). Allodynia refers to a feeling of pain in response to a normally harmless stimulus. For example, some individuals who have suffered nerve damage as a result of viral infection experience unbearable pain from just the light weight of their clothing. Hyperalgesia is somewhat related to allodynia in that the response to a painful stimulus is extreme. In this case, a mild pain stimulus, such as a pin prick, causes a maximum pain response. Phantom limb pain occurs after a limb is amputated; although an individual may be missing the limb, the nervous system continues to perceive pain originating from the area.

Causes & symptoms

Pain is the most common symptom of injury and disease, and descriptions can range in intensity from a mere ache to unbearable agony. Nociceptors have the ability to convey information to the brain that indicates the location, nature, and intensity of the pain. For example, stepping on a nail sends an information-packed message to the brain: the foot has experienced a puncture wound that hurts a lot.

Pain perception also varies depending on the location of the pain. The kinds of stimuli that cause a pain response on the skin include pricking, cutting, crushing, burning, and freezing. These same stimuli would not generate much of a response in the intestine. Intestinal pain arises from stimuli such as swelling, inflammation, and distension.

Diagnosis

Pain is considered in view of other symptoms and individual experiences. An observable injury, such as a broken bone, may be a clear indicator of the type of pain a person is suffering. Determining the specific cause of internal pain is more difficult. Other symptoms, such as fever or nausea, help narrow down the possibilities. In some cases, such as lower back pain, a specific cause may not be identifiable. Diagnosis of the disease causing a specific pain is further complicated by the fact that pain can be referred to (felt at) a skin site that does not seem to be connected to the site of the pain's origin. For example, pain arising from fluid accumulating at the base of the lung may be referred to the shoulder.

Since pain is a subjective experience, it may be very difficult to communicate its exact quality and intensity to other people. There are no diagnostic tests that can determine the quality or intensity of an individual's pain. Therefore, a medical examination will include a lot of questions about where the pain is located, its intensity, and its nature. Questions are also directed at what kinds of things increase or relieve the pain, how long it has lasted, and whether there are any variations in it. An individual may be asked to use a pain scale to describe the pain. One such scale assigns a number to the pain intensity; for example, 0 may indicate no pain, and 10 may indicate the worst pain the person has ever experienced. Scales are modified for infants and children to accommodate their level of comprehension.

Treatment

There are many drugs aimed at preventing or treating pain. Nonopioid analgesics, narcotic analgesics, anticonvulsant drugs, and tricyclic antidepressants work by blocking the production, release, or uptake of neurotransmitters. Drugs from different classes may be combined to handle certain types of pain.

Nonopioid analgesics include common over-the-counter medications such as aspirin, acetaminophen (Tylenol), and ibuprofen (Advil). These are most often used for minor pain, but there are some prescription-strength medications in this class.

Narcotic analgesics are only available with a doctor's prescription and are used for more severe pain, such as cancer pain. These drugs include codeine, morphine, and methadone. Contrary to earlier beliefs, addiction to these painkillers is not common; people who genuinely need these drugs for pain control typically do not become addicted. However, narcotic use should be limited to patients thought to have a short life span (such as people with terminal cancer) or patients whose pain is only expected to last for a short time (such as people recovering from surgery).

Anticonvulsants as well as antidepressant drugs, were initially developed to treat seizures and depression, respectively. However, it was discovered that these drugs also have pain-killing applications. Furthermore, in cases of chronic or extreme pain, it is not unusual for an individual to suffer some degree of depression; therefore, antidepressants may serve a dual role. Commonly prescribed anticonvulsants for pain include phenytoin, carbamazepine, and clonazepam. Tricyclic antidepressants include doxepin, amitriptyline, and imipramine.

Intractable (unrelenting) pain may be treated by injections directly into or near the nerve that is transmitting the pain signal. These root blocks may also be useful in determining the site of pain generation. As the underlying mechanisms of abnormal pain are uncovered, other pain medications are being developed.

Drugs are not always effective in controlling pain. Surgical methods are used as a last resort if drugs and local anesthetics fail. The least destructive surgical procedure involves implanting a device that emits electrical signals. These signals disrupt the nerve and prevent it from transmitting the pain message. However, this method may not completely control pain and is not used frequently. Other surgical techniques involve destroying or severing the nerve, but the use of this technique is limited by side effects, including unpleasant numbness.

Alternative treatment

Both physical and psychological aspects of pain can be dealt with through alternative treatment. Some of the most popular treatment options include acupressure and acupuncture, massage, chiropractic, and relaxation techniques, such as yoga, hypnosis, and meditation. Herbal therapies are gaining increased recognition as viable options; for example, capsaicin, the component that makes cayenne peppers spicy, is used in ointments to relieve the joint pain associated with arthritis. Contrast hydrotherapy can also be very beneficial for pain relief.

Lifestyles can be changed to incorporate a healthier diet and regular exercise. Regular exercise, aside from relieving stress, has been shown to increase endorphins, painkillers naturally produced in the body.

Prognosis

Successful pain treatment is highly dependent on successful resolution of the pain's cause. Acute pain will stop when an injury heals or when an underlying problem is treated successfully. Chronic pain and abnormal pain are more difficult to treat, and it may take longer to find a successful resolution. Some pain is intractable and will require extreme measures for relief.

Prevention

Pain is generally preventable only to the degree that the cause of the pain is preventable; diseases and injuries are often unavoidable. However, increased pain, pain from surgery and other medical procedures, and continuing pain are preventable through drug treatments and alternative therapies.

Key Terms

Acute pain
Pain in response to injury or another stimulus that resolves when the injury heals or the stimulus is removed.
Chronic pain
Pain that lasts beyond the term of an injury or painful stimulus. Can also refer to cancer pain, pain from a chronic or degenerative disease, and pain from an unidentified cause.
Neuron
A nerve cell.
Neurotransmitters
Chemicals within the nervous system that transmit information from or between nerve cells.
Nociceptor
A neuron that is capable of sensing pain.
Referred pain
Pain felt at a site different from the location of the injured or diseased part of the body. Referred pain is due to the fact that nerve signals from several areas of the body may "feed" the same nerve pathway leading to the spinal cord and brain.
Stimulus
A factor capable of eliciting a response in a nerve.

Further Reading

For Your Information

    Books

  • Adams, Raymond D., Maurice Victor, and Allan H. Ropper. Principles of Neurology. 6th ed. New York: McGraw-Hill, 1997.
  • Tollison, C. David, John R. Satterthwaite, and Joseph W. Tollison, eds. Handbook of Pain Management. 2nd ed. Baltimore: Williams & Wilkins, 1994.

    Periodicals

  • Iadarola, Michael J., and Robert M. Caudle. "Good Pain, Bad Pain: Neuroscience Research." Science 278 (1997): 239.
  • Markenson, Joseph A. "Mechanisms of Chronic Pain." The American Journal of Medicine 101 (supplement 1A/1996): 6S.
  • Sykes, J., R. Johnson, and G.W. Hanks. "Difficult Pain Problems: ABC of Palliative Care." British Medical Journal 315 (1997): 867.

    Organizations

  • American Chronic Pain Association. P.O. Box 850, Rocklin, CA 95677-0850. (916) 632-0922. http://members.tripod.com/~widdy/ACPA.html
  • American Pain Society. 4700 W. Lake Ave., Glenview, IL 60025. (847) 375-4715. http://www.ampainsoc.org/

Gale Encyclopedia of Medicine. Gale Research, 1999.

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