Physiology of pain

It is always will be vitally important to listen to the patient who reports pain. But pain does not stop there. Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life. It is unquestionably a sensation in a part of the body, but it is also unpleasant, and therefore also an emotional experience. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons, there is a lot know about pain to understand it properly, not just how it occurs or how will it stop but the whole mechanism behind it, i.e. how the body react to a pain, how the sensation reach the brain and how the brain actively stop it, is what called all about physiology of pain.

Peripheral receptors

According to the response of the reseptors here they make two important distinction between pain: There are two distinct responses to a painful stimulus, a "first pain" and a "second pain". The first pain is well-localised and brief, the second is more diffuse and protracted.

First pain is described as sharp, and "pricking". It localises to a well-defined part of the body surface.The receptors for this first pain are high threshold mechanoreceptors. There appear to be specific "nociceptors" which mediate pain, and ONLY pain.

Second pain is due to stimulation of receptors that exist in many tissues (but not in, paradoxically, the brain). It is often described as dull (i.e. not sharp) and aching. It is poorly localised. Receptors for this second pain are termed polymodal nociceptors. This pain tends to last beyond the termination of an acute painful stimulus. Sources, pathways, perception of and treatment of the two types of pain are very different. Visceral pain is predominantly of the "second pain" type.

Neural pathways.

As soon as the pain occurs in case of "first pain" responses are conveyed from the injured part of body to the dorsal horn (define) of the spinal cord in small myllinated fibres (define) (delta A fibre), while in case of "second" pain is conveyed in non-mylinated C fibres.

Spinal cord pathways.

This is indeed a complex process as per IASP consideration the response work in the spinal cord as follows:

  1. Initial connections: the fibres carrying the responses enter the spinal cord where layers of the spinal gray matter present.
  2. Local interconnections occur.
  3. Ascending pathways and descending (control) pathways are considered happens much later.

At the site of spinal cord about 70% of pain fibres enter in the dorsal root, but the rest enter the ventral (motor root).the gray matter of spinal cord has 10 lamina/layers, (I-X). The unmyelinated C fibres carrying response of second pain synapse in layer I to V while A delta fibres carrying response of first pain synapse. These different routes are only the start of dramatically different pathways! The two main pathways are:-

The primitive type is spino-reticulo-diencephalic tract, here impulses pass from type C fibres to several "second order" neurons.

Important second order neurons-
  1. nerve cells that are not committed to responding only to pain, responding also to gentle stimuli and increasing their response as the stimulus becomes more marked.
  2. Nociceptive specific neurones found in lamina I, responding only to noxious stimuli;
  3. Complex neurons which receive numerous inputs and have been poorly studied. They are seen mainly in laminae VII and VIII.

The more modern neospinothalamic tract, this takes most of its fibres from Laminae I and V, and appears to mediate "first" pain.

Spinal pathways (local interconnections) - there are several important interaction between the spinal cord and the impulses, one of great importance are connections mediating so-called "gating". The basic idea here is that "painful stimuli" coming into the spinal cord via C fibres can be modified by other inputs, which "close the gate on the incoming pain". These inputs come from: A delta fibres, A beta fibres and Others.

This arrangement has several practical consequences:

  1. Transcutaneous Electrical Nerve Stimulation (TENS) works
  2. Dorsal column stimulation (DCS) works
  3. Acupuncture works!
  4. Rubbing the skin locally locally helps decrease pain!

Higher ascending pathways- the old spino-reticulo-diencephalic pathway ends in the reticular system of the brain stream, but sends fibres to the thalamus also. The important thing is connection between the reticular system and the hypothalamus (and thalamus)-these may explain autonomic components of the pain response. Emotional'/affective responses to pain may be explained by projections that go from thalamus to most of the cortex.the basal ganglion may also involed in pain discrimination, the affective component of pain, and even in pain modulation.

The fresh, new "spinothalamic tract"- nips up to the ventrobasal part of the lateral thalamus. The connection go from here to the sensory cortex, which precisely help to locate the region of somatic pain. But this is not the main pian pathway,because lesions along the pathway do not cancel out the sensation of pain,infact may cause severe pain,known as "thalamic syndrome"-possibly due to damage to inhibitory pathways.Descending pathways.

Descending modulation of pain sensation originates from three main areas:

  • Cortex;
  • Thalamus;
  • Brainstem, where the Periaqueductal grey matter (PAG) is particularly important.
  1. Fibres pass from PAG to the reticular formation of the medulla where connections are serotoninergic, and from there axons descend in the "dorsolateral funiculus" of the spinal cord, to end up on interneurones right next to the lamina II in the cord. The synapses here are enkephalinergic(define).Stimulation of this system causes inhibition of incoming pain impulses. Thus, although serotonin applied peripherally augments pain, its action centrally is important in descending inhibition of incoming painful impulses!
  2. There is a separate pathway which inhibits pain based on noradrenaline which make matters more complex, quite apart from the above inhibitory pathway that works mainly on opiates,. Noradrenaline-based projections appear to come from the NRM(the nucleus raphe magnus), and also from the locus coeruleus in the pons(define). This is one explanation why antidepressants (which inhibit noradrenaline uptake) may be effective in controlling pain, but it is impotant toremember that antidepressants also inhibit serotonin uptake, so they may also increase activity in the fibres that pass from PAG (Periaqueductal grey matter) to medulla!
  3. "On" and "Off" cells:

There are probably two main classes of neurones in the PAG and VMM (ventromedian medulla):

"On" cells increase pain transmission;

"Off" cells decrease it.

Opioids tends to inhibit "on" neurones and increase transmission in "off" neurones, as well as noradrenaline also inhibits "on" neurons.

The response to pain.

There is a marked difference in responses to visceral pain from those evoked by somatic pain. Visceral pain generally results in tonic muscular spasm (to decrease movement of the affected area) while somatic pain usually causes withdrawal of the affected part of the body ("to protect this region from further damage"). The sensation obtained by these two are also different.

We are all also aware that pain (be it somatic or visceral) can have profound autonomic effects. Some of the reasons for this have been state that, there is a good degree of cross-over between the somatic and visceral systems, notably at the level of the WDR cell (Wide Dynamic Range cell, An important property of this neurons is "wind up") and "complex neurone" in the spinal cord, but also extensively at higher centres, with projections to, for example, the hypothalamus. Also of note is the close relationship between sensory afferents and sympathetic outflow (See Cross, 1994). Recent studies suggest that epidural fentanyl alone blocks the neurohormonal response to surgery (See Harukuni, I et al. anesth Analg. 1995(81)1169)!

A brief note on opiates and their receptors

There are three main types of opioid receptor: delta, kappa and mu. All of these are widely distributed in the brain, and are not only concerned with modulation of pain perception, but also with a variety of other functions. This explains why in trying to control pain, as researcher have encounter many unwanted side-effects. For example, mu receptors are widespread in the brainstem parabrachial nuclei (where stimulation of them causes respiratory depression), and dependence may be related to receptors in the locus coeruleus and ventral tegmentum. There are different receptors which are mainly concerned with pain and respiratory depression, respectively, but this is probably too simplistic.

Opioids work in two main ways:

  • They either block neurotransmitter release (by inhibiting calcium influx into the presynaptic terminal),
  • Hyperpolarise neurones by opening a potassium channel (and therefore effectively temporarily knock the neurone out of action)!
  • Corresponding (more-or-less) to the three receptor classes, there are three main groups of endogenous opioids: the enkephalins, endorphins and dynorphins.

  • Enkephalins act mainly on delta receptors,
  • dynorphins on kappa receptors,
  • beta endorphin acts on both mu and delta receptors.
  • Morphine is almost exclusively a mu agonist.

Mu and delta receptors appear to be expressed on the same cells, and stimulation of one receptor increases the affinity of the other! Beta endorphin is also a "neurohormone" in that it may have distant effects on neurones with mu receptors, after being released in the hypothalamus.

The effect of opioids on the "on" and "off" cells in the medulla is most interesting: ONLY the "on" cell is affected by opioids - it is inhibited, probably by hyperpolarization due to opening of potassium channels. The "off" cell certainly becomes more active in the presence of opioids, but this is only secondary to the lessened activity of the "on" cell. The "on" cell is also inhibited by the alpha-2 agonist clonidine. In fact, in some cells the mu receptor and the alpha-2 receptor are linked to the same G protein and the same potassium channel! Of even more interest is evidence that by giving morphine we can activate endogenous circuitry that turns on enkephalin release!

The roles of the various types of opiate receptor have recently been clarified by studies in opiate receptor knockout mice. Mu-receptor knockout mice had shorter latencies on tail-flick and hot plate tests, than did wild-type mice, and morphine did not reduce responses to pain. These studies support the contention that the mu receptor is the main player in morphine-induced analgesia.


It is an unpleasant sensation, which generally occurs due to potential tissue damage, it can be acute or chronic; It can be a minor inconvenience or completely disabling. The sensation is borne by the combine action of the area of injury and how the brain deals with signals from the area of pain.Pain motivates us to withdraw from damaging or potentially damaging situations, protect the damaged body part while it heals, and avoid those situations in the future. Most pain resolves promptly and the body has healed, but sometimes pain persists despite removal of the stimulus and sometimes pain arises in the absence of any detectable stimulus, damage or pathology. There are some psychological regions which also effect pain such as, social support, cultural values, hypnotic suggestion, distraction, and appraisal can all significantly modulate pain's intensity or unpleasantness. Pain basically divided into two types-

Acute- Pain that lasts less than 30 days, lasting only until the noxious stimulus is removed or the underlying damage or pathology has healed such as, headache.

Chronic- Pain that persist for more than six month, popularly known as pain that extends beyond the expected period of healing. Such as. Cancer and benign. It is also subdivide into subacute pain, which lasts from one to six months.

Pain significantly affect quality of living and general functioning of a person's, so it is very important to tackle it in every possible way. As far as medication of pain is concerned it is a common headache of all physician round the world to develop useful drugs and therapies to cure pain, some of such medical specialties as anesthesiology, physiatry, neurology, palliative medicine and psychiatry. The study of pain has in recent years attracted many different fields including pharmacology, neurobiology, nursing, dentistry, physiotherapy, and psychology etc.

The problem arises due to inadequate treatment of pain, which is widespread throughout surgical wards, intensive care units, and accident and emergency departments. The management of all forms of chronic pain including cancer pain, and in end of life care. This negligence is found in all ages, from neonates to the frail elderly. In September 2008, the World Health Organization (WHO) estimated that approximately 80 percent of the world population has either no or insufficient access to treatment for moderate to severe pain. Every year tens of millions of people around the world, including around four million cancer patients and 0.8 million HIV/AIDS patients at the end of their lives suffer from such pain without treatment. Yet the medications to treat pain are cheap, safe, effective, generally straightforward to administer, and international law obliges countries to make adequate pain medications available to all at right time and reasonable cost.

Reasons for lack of discipline in pain management include cultural, societal, religious, and political attitudes, including acceptance of torture. Moreover, the biomedical model of disease, focused on path of physiology rather than quality of life, however some strategic steps must be taken for a betterment of this system.

Strategies currently applied for improvement in pain management include

  • Framing it as an ethical issue;
  • Promoting pain management as a legal right,
  • Providing constitutional guarantees and statutory regulations that span negligence law,
  • Criminal law, and elder abuse;
  • Defining pain management as a fundamental human right,
  • Categorizing failure to provide pain management as professional misconduct,
  • Issuing guidelines and standards of practice by professional bodies.

The treatment of pain also face troubles as the tolerance of pain varies greatly from one person to another. For this reason, one medication will not be right for everyone with the same injury. For example, some people are quite happy with an over-the-counter medication for an ankle sprain, while others will need a more powerful prescription pain reliever .Generally, medications try either to stop the transmission of pain from the site of injury or to affect the brain directly.

The International Association for the Study of Pain (IASP) synthesizes much of the above and recommends describing pain according to five categories:

  • Its anatomical location (neck, lower back, etc.),
  • The body system involved (gastrointestinal, nervous, etc.),
  • Temporal characteristics (intermittent, constant, etc.),
  • Intensity and time since onset,
  • Etiology (cause).

However this IASP system has been criticized by some scientists as inadequate for guiding research and treatment. They propose the development of an additional category based, not on symptoms or underlying conditions, but on the type of neurochemical mechanism generating the pain. According to its location in the body Pain can be classified into,

  • Angina
  • Back pain
  • Children and pain
  • Cancer pain
  • Diabetic neuropathy
  • Fibromyalgia
  • Headache
  • Leg pain
  • Multiple sclerosis
  • Migraine
  • Nociceptive
  • Neuropathy
  • Osteoarthritis
  • Rheumatoid arthritis
  • Post herpetic neuralgia
  • Postoperative pain



Angina is a chest pain caused by the narrowing of blood vessels in the heart. This happens when less amount blood is able to pass through the the heart, so the heart revieves less oxygen. It is more likely to happen when a person is at most active state like, Exercise, smoking, overeating, cold and damp places, and being worried or unhappy may cause the symptoms of angina.

Angina may be caused by any condition that affects the blood flow to your heart, such as:

  • coronary artery disease, in which the walls of the arteries that carry blood to the heart become hardened (called atherosclerosis) because of fatty deposits - this restricts the flow of blood, so less oxygen reaches the heart muscle, and is by far the most common cause of angina.
  • coronary artery spasm (a temporary narrowing of a coronary artery causes blood to slow or stop flowing through the artery - when the spasm stops, the artery and blood flow return to normal.
  • Blockage of a coronary artery by a blood clot or by compression from something outside the artery.
  • Inflammation or infection of the coronary arteries.
  • Injury to one or more coronary arteries.
  • Poor functioning of the tiny blood vessels of the heart (microvascular angina).
  • As angina occurs when a person is at active state, there are certain causes which "triggers" angina such as,

    Physical exertion or exercise, emotional stress, exposure to cold, decreased oxygen content in the air you breathe, and when flying in an airplane or being at high altitude. Using a stimulant, such as caffeine, or smoking a cigarette (which lowers the amount of oxygen in the blood).

    Above activity are the resoin for the onset of pain, after the angina symptoms progress as follows-

  • A feeling of tightness, dull ache, or heaviness begins in the chest region. This sometimes spreads to the neck, shoulder, and down the arms (especially the left arm).
  • The pain or discomfort usually begins slowly and then reaches a peak after several minutes.
  • Most patients have a reduction in pain or discomfort after a period of rest or after receiving medication called a nitrate.
  • Some people have the following additional symptoms:

  • Difficulty in breathing.
  • Feeling faint.
  • Feeling sick.
  • Severe tiredness.
  • Weakness.

Unstable angina is a particular form of angina that becomes quite debilitating over a short period of time. It may happen more and more often and be more severe and last longer, and it may occur at resting state. Medication may not work as well. The pain is very severe.

It is better to get help of a docter on the onset of any of the above symptoms before it get worsen. People with untreated unstable angina are at high risk of a heart attack. Recognising unstable angina and treating it properly greatly reduces these risks. Sometimes it is hard to tell a severe attack of angina from the beginning of a true heart attack. Call 999 or your emergency doctor right away if:

  • you are sweating a lot during an attack of angina;
  • you have chest discomfort (pressure, fullness, squeezing, or pain) that lasts more than 10 minutes or goes away and comes back;
  • you have chest discomfort with light headedness;
  • you still have pain after taking three nitrate tablets at 5 minute intervals
  • Several tests can be used to confirm a diagnosis of angina, these tests may include

  • an electrical measure of heart activity (an ECG),
  • an exercise stress test (where you have to run or walk on a treadmill and the effects on your heart are measured using the ECG),
  • a special ultrasound called an echocardiogram to create a picture of the heart,
  • an angiogram, where dye is injected into the coronary (heart) arteries to look for any blockages,
  • a test that measures fat (cholesterol) levels in the blood, and a blood test that measures specific heart muscle chemicals.

One important thing must be remembered before and during tests is smoking, drinking and drug use can alter your test results.

Nociceptive pain

This pain generally arise due to damage of nocicepters, a nociceptor is a sensory receptor that reacts to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.This pain may be again classified in to different forms according to the mode of noxious stimulation; the most common categories being "thermal" (heat or cold), "mechanical" (crushing, tearing, etc.) and "chemical" (iodine in a cut, chilli powder in the eyes).

Nociceptive pains may also be divided into "superficial" and "deep", Superficial pains are initiated by activated on the skin and are sharp, well-defined, clearly localized pains. Examples of injuries that produce superficial pain include minor wounds and minor (first degree) burns. Deep pains are initiated by stimulation in ligaments, tendons, bones, blood vessels, fasciae and muscles, and are dull, aching, poorly-localized pains; examples include sprains, broken bones and myofascial pain (extremely painful "knots" found in any skeletal muscle of the body). Visceral pains originate in the viscera (organs) and are usually more aching or cramping than deep pains. Visceral pains may be well-localized, but often they are extremely difficult to locate, and several visceral regions produce "referred" pain when injured, where the sensation is located in an area completely unrelated to the site of injury.

Neuropathic (Nerve) Pain

This pain may occur when there is either damage to or dysfunction of nerves in the peripheral or central nervous system for that reason faulty signal are sent to the brain and experienced as pain. Neuropathic pain can be either outside the central nervous system or central in origin, it includes diabetic neuropathy, trigeminal neuralgia, postherpetic zoster pain (peripheral pains), and the thalamic pain syndrome (a central pain). Neuropathic pain frequently coexists with nociceptive pain few examples include trauma that damages tissue and nerves, burns (that burn skin as well as nerve endings), and external nerve compression. Such as tumor nerve compression and sciatica from herniated discs pressing on nerves. Neuropathic pain is often described as having a burning or electrical quality. It may feel like a shock or lightning bolt. Diabetic neuropathy commonly results in this type of sensation.

Neuropathic (Nerve) Pain

This pain may occur when there is either damage to or dysfunction of nerves in the peripheral or central nervous system for that reason faulty signal are sent to the brain and experienced as pain. Neuropathic pain can be either outside the central nervous system or central in origin, it includes diabetic neuropathy, trigeminal neuralgia, postherpetic zoster pain (peripheral pains), and the thalamic pain syndrome (a central pain). Neuropathic pain frequently coexists with nociceptive pain few examples include trauma that damages tissue and nerves, burns (that burn skin as well as nerve endings), and external nerve compression. Such as tumor nerve compression and sciatica from herniated discs pressing on nerves. Neuropathic pain is often described as having a burning or electrical quality. It may feel like a shock or lightning bolt. Diabetic neuropathy commonly results in this type of sensation.

One of the most important form of it, is diabetic neuropathy, i.e, a nerve damage caused due to diabetes, due to which the nerves are somehow become unable to carry massages to the brain and other parts of the body, which effects some body function such as, heart rate, digestion and sweating. This type is called autonomic neuropathy. It occurs with both type of diabetes. The most common symptoms of it are loss of feelings, weakness in the hands, legs, feet and arms. Diabetic neuropathy affect body function more compare to other less common types of neuropathy are:proximal neuropathy, Focal neuropathy .

Proximal neuropathy - it starts with pain in either the thighs, hips, buttocks, or legs, usually on one side of the body. This type of neuropathy is more common in those with Type 2 diabetes and in older people. where legs will feel weak, and you will need help to get from a sitting to a standing position.

Focal neuropathy- it is painful and unpredictable. But it tends to improve by itself over weeks or months, and does not cause long-term damage. It occurs most often in older people.

People with diabetes are also prone to tend to develop nerve compressions, which cause so-called entrapment syndromes. One of the most common is carpal tunnel syndrome, with numb and tingling hands, and sometimes muscle weakness or pain. Other nerves susceptible to entrapment may cause pain on the outside of the shin or the inside of the foot.

People with diabetes can develop nerve problems at any time, but the a person having Type 1 diabetes for a longer period are more at risk, whereas with Type 2 diabetes, neuropathies are more likely to develop sooner commonly in two cases

  1. Around half of all people with diabetes have some form of neuropathy, but not all have symptoms.
  2. People who have had problems controlling their blood glucose levels, those with high levels of blood fat and high blood pressure, low levels of insulin. It is thought that these cause chemical changes in nerves that impair the nerves' ability to transmit signals, also in overweight people, and those people over the age of 40, diabetes-related damage to the blood vessels that carry oxygen, nutrients to the nerves and autoimmune disease factors that cause inflammation in nerves.

The symptoms of autonomic neuropathy include:

  • low blood pressure and dizziness when you rise quickly from sitting or lying down;
  • rapid or irregular heart beats;
  • constipation or diarrhoea;
  • nausea or vomiting;
  • trouble swallowing;
  • Trouble having an erection, in a man, or vaginal dryness in a woman.

Normally, symptoms such as shakiness occur when blood glucose levels drop below 4 mmol/l. This acts as a warning signal that your blood sugar levels are low. In people with autonomic neuropathy, these symptoms may not occur, making hypoglycaemia difficult to recognise.Another effect of autonomic neuropathy is that nerves no longer control the heart rate properly, so that it may stay high, instead of rising and falling in response to normal body functions and exercise. When this happens, the high blood pressure that results can damage blood vessels, especially thin-walled ones at the extremities, such as in fingers and toes. Urinary incontinence may result from autonomic nerve damage because a person may not be able to sense when the bladder is full or control the muscles that release urine.

If the nerves in your legs and feet get damaged, you may not be able to feel normal pain in those parts of your body, due to this reason you may not feel the sensation or pain due to injury, in addition to it your muscles might show atrophy (decrease in muscle size), which cause trouble in walking. This will became more dangerous when your feet develop sours. If these sores get infected, possibly your foot have to be removed if not treated in right time. Diabetes increase the risk of infection as it takes a lot of time for an injury to heal in case of diabetes. One must consult a docter at the onset of any of these symptoms, by which a docter will be able to start the treat at the right time and prevent further damage.


One of the most common type of pain is headache and is rarely a sign of a serious problem, that is the pain occur in head. This is two types, "normal" headache, also known as tension or stress headache, another type is cluster headaches are a lasting pain felt in head. Headaches can occur once awhile, rarely, daily , depending on type and cause. It can be felt in only one part of the head, may be in both part of the head and sometimes it can move from one part of the head to another.

Tension headaches- it occurs occasionally and can last from half an hour to a week, while cluster headaches are frequent headache. Tension headaches are more common compare to cluster headache. Occurrence of Both seems to have different cause .

A person feel headache, when the blood vessels in the head widen and narrow for a little time. There are different resions behind different pains as:

Tension headache rise due to, emotional stress,lack of sleep, eating or consumption of alcohol too much work that makes you tired, anxiety or depression, eye strain (including sun glare), use of drugs or alcohol, allergic reactions, food additives, and exposure to fumes and chemicals.If a person have a low blood sugar level, can get a headache if not eat properly.

Anyone can have a tension headache, but they are more common in adults. Women are more likely to get tension headaches, because of changes in their hormonal cycle. Tension headaches tend to run in the family.

Symptoms of headache includes :-

  • Moderate pain in the front or back of the head.
  • Tightness in the neck or scalp.
  • Constant pain over the sides of the head (feeling like your head is in a clamp).
  • Throbbing pain all over the face.
  • Pain in the head that is present when you wake up.
  • Pain in the head that interrupts your sleep.

However cluster headache tends to occur more oftenly in people who are Heavy smokers and men over the age of 30. Women who have cluster headaches are more likely to have a history of migraine. Head injury can also cause cluster headaches.Cluster headaches seem to have a different cause than tension headaches. Cluster headaches thought to occur when there is an imbalance of chemicals (neurotransmitters) in the brain. symptoms of cluster headache includes:-

  • A headache during which the pain steadily gets worse during the first 15 minutes and then lasts for up to 3 hours.
  • Severe pain in the front, or on one side of the head - the headaches of one cluster all occurring in the same part of the head.
  • Pain around one or both eyes.
  • Up to eight headaches a day, during a cluster period that lasts for one to four months, then does not recur for many months or years.
  • Pain that occurs at almost the same time every day over several days - this is often at night.

Chronic headaches are simply prolonged or very frequent headaches, however chronic pain is more common compare to chronic cluster pain. Though headache is the most common type of pain but steel it may have very dangerous reprecations if not treated or wrongly diagnosed. A person must concern a docter if any of the following cases:-

  • you get a sudden very severe headache, unlike any you've had before;
  • you are getting severe or frequent headaches;
  • you get a sudden, severe headache and a stiff neck develops soon afterwards;
  • The headache is accompanied by a stiff neck, fever, nausea, vomiting, drowsiness and confusion.

It known as the most severe form of headache, which can last from 2 hours to three days and usually comes with other symptoms, such as nausea, vomiting and vision problems. However its occurrence differ from person to person. In some it occur weekly; others may have them only once in a while, perhaps even less than once a year.

Previously it was believed that migraine occurs due to a temporary narrowing and then widening of the blood vessels that go to the scalp and brain. But according to scientists, it is now reveled that It seems that low levels of a brain chemical called serotonin may develop migraine headaches in people. Though most migraine occurs spontaneously but certain substances or events are believed to trigger the imbalance of neurotransmitters that can lead to migraine. Person suffering from migraine has inherited a sensitive nervous system that under certain circumstances can cause a migraine.

There are certain "circumstances" which activate migraine, such as:

  • Tiredness.
  • Changes in the weather (barometric pressure).
  • Certain foods, such as wine, cheese or chocolate (different foods affect different people).
  • Monosodium glutamate (MSG) or other food preservatives, such as nitrates.
  • Bright lights.

Other factors like Stress can also trigger a migraine, but the headaches don't always coincide with the emotional upset: sometimes they occur days after the stress. Lack of sleep or too much sleep can trigger a migraine. So can the use of many prescription and non-prescription drugs.

The condition affects both men and women, but occurs more often in women. This is because migraines can be triggered by fluctuating hormones during the menstrual cycle or by the use of birth control pills.Having a family history of migraine increases the risk.

The nature of migraine attack can vary from on person to other, but there is a sequence of classical migraine:-

  • Headache is preceded by special symptoms, which last for a short time for about 15 minutes to an hour can include symptoms like, temporary partial blindness, visual or hearing differences, hunger and thirst. For example, people often see bright spots or zigzag patterns in front of their eyes. These symptoms are collectively called aura and they can act as a warning that a migraine is coming on.
  • The aura symptoms usually disappear once the headache begins, although there is sometimes overlap. A dull pain develops in the side of the head. The pain may spread to the entire head, but it may remain more severe on one side of the head.

The pain becomes intense and throbbing. Nausea and vomiting may occur. Some people have blurred vision or become extremely sensitive to light, or may develop a numbness or tingling of the face or one arm.

Some people may only get some of these symptoms or their timing may be different. Indeed, the majority of migraine sufferers may not get an aura. A few people may experience vision or stomach problems without the headache; this is more likely in older people.

A person must concerned a docter when any of these problems occurs, neck stiffness, confusion with the headache, a sudden change in your migraines such as attacks coming more often, or a treatment not working, nervous system problems, such as difficulty in walking or disturbed vision, between attacks, a high temperature with the headache, a rash that does not disappear when you press it (glass test), local tenderness at the side of your head or pain when you brush your hair. Diaries can be used to help your doctor confirm a diagnosis of migraine, and also, if you carry on keeping the diary during treatment, to see if a treatment is working.

A headache diary include data's like,

  • timing of each attack - how frequently they occur and how long they last;
  • type and location of the pain (for example, dull, sharp, throbbing, or a feeling of pressure behind the eyes);
  • any symptoms before the headache began;
  • foods and drinks you had before the headache began (you need to check the ingredients lists to look for possible triggers);
  • use of cigarettes, caffeine, alcohol or carbonated drinks before the headache began;
  • time you went to bed and time you got up before the headache began;
  • if you are a woman, your menstrual periods and use of birth control pills or other female hormones.
Multiple sclerosis (MS) -

Sclerosis means hardening, this is an illness which affects nerve cells in the brain and spinal cord and is a progressive illness. Normally, nerve cells are protected by a sheath of myelin, a fatty material that also helps speed the passage of nerve impulses. When the myelin sheath becomes damaged or inflamed, it cause disrupts nerve signals, causing a variety of symptoms. It is believed to be an autoimmune illness. This means that the body's own immune system, which normally fights against infections, attacks itself. In this case, it attacks the myelin sheath which coats the nerves. So the nerves get damaged and become scarred or hardened.

The precise cause of MS, that is, the reason for the autoimmune response, is unknown. There may be more than one cause, because the evidence suggests that there are both genetic (inherited) and environmental factors that lead to MS.

Symptoms depend on which part of the brain or spinal cord is affected. Common symptoms of brain involvement include:

  • Sudden loss of vision or blurry vision.
  • Clumsiness.
  • Lack of coordination.
  • Slurred speech.
  • Feeling very tired.
  • Muscle weakness.
  • Difficulty walking.
  • With spinal cord involvement, common symptoms include:

  • Loss of bladder control.
  • Feeling numbness or tingling in the arms or legs.
  • Weakness or a 'heavy' feeling in the arms or legs.

Usually, these symptoms periodically worsen and then improve. The periods when symptoms suddenly get worse are called relapses and the periods when you feel much better are called remissions.However it has also been suggested that infections may trigger actual relapses of MS. As a result, some people with MS have tried to avoid infections through immunization. There is no easy answer here, since immunizations are thought to sometimes trigger a relapse.

If person have any of these symptoms of MS should see a doctor. The symptoms may well indicate a problem other than MS, but they actually suggest a condition that is affecting the nervous system in some way, whether or not it is simply stress or something more serious such as MS, which should always be investigated, and treated at the right time.

Rheumatoid arthritis

Rheumatoid arthritis is an illness that causes painful inflamed joints. It usually starts between the ages of 22 and 55years, and is over twice as common in women as in men. Any joint can be affected. The actual reason of rheumatoid arthritis is not known, but it is a auto immune condition. This means that the body's defense system against disease attacks healthy cells instead.

In case of rheumatoid arthritis the body's own antibodies attack the membranes around joints (synovial membranes), causing swelling, pain, stiffness and in some cases, deformity. There is also inflammation of the sheaths around tendons (which join muscles to bones). Eventually, there may be erosion of the smooth articular cartilage, which covers the ends of the bones in joints, or there may be erosion of the bone itself.

The rheumatoid arthritis is a self damage illness, there are symptoms, which describe its activity more, the most common symptoms are joint pain and stiffness that are worse after waking up and after r a long period of sitting. The stiffness usually gets better with movement. The symptoms tend to come and go and can range from mild to severe. Other symptoms include:

  • Burning/itching eyes.
  • Fatigue.
  • Fever.
  • Joint redness.
  • Joint swelling.
  • Joint tenderness.
  • Joint deformity.
  • Joint warmth.
  • Leg ulcers.
  • Loss of appetite.
  • Numbness/tingling.
  • Shortness of breath.
  • Skin nodules.
  • Weakness.

The first symptoms of rheumatoid arthritis tend to be felt in small joints, such as ankles and knuckles. Often both sides of the body are affected at the same time, a feature that is used to help with diagnosis.


Osteoarthritis is a disorder of the joints Osteoarthritis is characterised by progressive wearing away of the cartilage of the joint. It mostly affects knees, hips, and the spine, but it can also affect other joints, like those in the hand. It is not the same as rheumatoid arthritis. With rheumatoid arthritis, the body's own antibodies attack the membranes around joints, and the sheaths around tendons that join muscles to bones. So rheumatoid arthritis is an autoimmune disease, whereas with osteoarthritis, the immune system has only a small part to play in the disease process.

Normally joint surfaces are covered with a smooth layer of cartilage, which is an elastic material, and bathed by a liquid called synovial fluid, a membrane called the synovium prevent it from leaking away from the joint (or joint capsule). Together, the cartilage and synovial fluid provide a cushion where two bones join together and stop them from rubbing against each other.

The cartilage maintains the right level of cushioning strength through the interaction between two chemicals: proteoglycans and collagen.

Proteoglycans absorb water into the cartilage, making it springy when compressed.

Proteoglycans are held in a collagen mesh, which keeps the cartilage elastic.

Because of its nature, cartilage act as a load-bearing covering on joints and is subjected to a lot of wear and tear.That is, it is constantly being eroded away by the activities of everyday living.

  • Normally, the body removes the worn out cartilage with the help of enzymes.
  • At the same time, the body is constantly reconstructing new cartilage.

As long as these two processes remain in balance, joints remain healthy. In osteoarthritis, more cartilage is worn away than repaired.It is not known why some people get osteoarthritis and others do not, but it is known that one of the proteins in synovial fluid is abnormal in people with osteoarthritis. This may make it less effective as a shock absorber.

The disease process of osteoarthritis may begin with a small amount of erosion of the cartilage. This leads to imbalance between the proteoglycans and collagen. More water goes into the cartilage, which becomes less effective at cushioning the joint. The cartilage becomes more susceptible to wear and tear, and gets thinner. Small projections form on the surfaces of the bones as they attempt to repair the damage, but they fail to do so.

A sequence of complicated, linked events work to help the body, ultimately bringing proteins and phagocytes (white blood cells that engulf and digest foreign material and debris) to the affected area to help to repair damaged tissue.

In osteoarthritis, the inflammatory response can make the osteoarthritis worse. The large number of inflammatory cells and substances within the joint cause irritation and swelling of the synovium. This stretches and may eventually thicken.

It was once thought that osteoarthritis was simply due to wear and tear. It is still a elusion that osteoarthritis is something you get in old age if you had an active youth or did a lot of manual work through your life. But it really is not that simple. Osteoarthritis is certainly more likely if you have given your joints a lot of wear and tear, especially if this is repetitive, and it is also associated with injury, trauma and obesity.

In particular, osteoarthritis becomes more common as we age, and is extremely common on X-ray when we reach our 70s.

However, many people who run and play competitive sports have no problems with arthritic joints and not everyone who is old gets arthritis. It is now understood that osteoarthritis is not an inevitable part of ageing or playing sports.

It seems as though a combination of different factors leads to the development of osteoarthritis in individuals. In different people, different combinations of factors may be important, but it is unusual to have just one underlying problem that causes osteoarthritis. Osteoarthritis affects both men and women, and there may be genetic factors involved.

Back pain-

Pain in the lower back or low back pain is a common concern, low back pain is not a specific disease. Rather, it is a symptom that may occur from a variety of different processes. In up to 85% of people with low back pain, despite a thorough medical examination, no specific cause of the pain can be identified.

Back pain can have many underlying reasons, but often no specific cause will be found and the pain will stop. There are many of the causes of back pain and proper evaluation and diagnosis. It is important to determine the appropriate diagnostic and treatment plan for particular circumstances.

  • Low back pain is second to the common cold as a cause of lost days at work. It is also one of the most common reasons to visit a doctor's office or a hospital's emergency department.For 90% of people, even those with nerve root irritation, their symptoms will improve within two months no matter what treatment is used, even if no treatment is given.
  • Usually back pain is refer as acute by doctors, if it has been present for less than a month and chronic if it lasts for a longer period of time.
  • Common causes of back pain involve-
  • Disease or injury to the muscles, bones, and/or nerves of the spine.
  • Pain arising from abnormalities of organs within the abdomen, pelvis, or chest may also be felt in the back. This is called referred pain.
  • Many intra-abdominal disorders, such as appendicitis, aneurysms, kidney diseases, bladder infections, pelvic infections, and ovarian disorders, among others, can cause pain referred to the back.
  • Normal pregnancy can cause back pain in many ways, including stretching ligaments within the pelvis, irritating nerves, and straining the low back.

The doctor must have these in mind when evaluating pain. Another important type of back pain is,Nerve root syndromes this is a pain that produce symptoms of nerve impingement (a nerve is directly irritated), often due to a herniation (or bulging) of the disc between the lower back bones. Sciatica is an example of nerve root impingement. Impingement pain tends to be sharp, affecting a specific area, and associated with numbness in the area of the leg that the affected nerve supplies.

Herniated discs are produced due to degeneration or thinning of the spinal discs. The jellylike central portion of the disc bulges out of the central cavity and pushes against a nerve root. The intervertebral discs begin to degenerate when a person suffering with this diease enters into his 30s. Herniated discs are found in one-third of adults older than 20 years of age. Only 3% of these, however, produce symptoms of nerve impingement.

Spondylosis occurs as intervertebral discs lose moisture and volume with age, which decreases the disc height. Even minor problems under these circumstances can cause inflammation and nerve root impingement, which can produce classic sciatica without disc rupture.

Spinal disc degeneration along with disease in joints of the low back can lead to spinal-canal narrowing (spinal stenosis). These changes in the disc and the joints produce symptoms and can be seen on an X-ray. A person with spinal stenosis may have pain radiating down both lower extremities while standing for a long time or walking even short distances.

Cauda equina syndrome is a medical emergency whereby the spinal cord is directly compressed. Disc material leaks into the spinal canal, which compresses the nerves. A person would experience pain, possible loss of sensation, and bowel or bladder dysfunction. This could include inability to control urination causing incontinence or the inability to begin urination.

Musculoskeletal pain syndromes that produce low back pain include myofascial pain syndromes and fibromyalgia.

Myofascial pain is characterized by pain and tenderness over localized areas (trigger points), muscle groups loss their range of motion in the particular area involved, and pain radiating in a characteristic distribution but restricted to a peripheral nerve. Relief of pain is often reported when the involved muscle group is stretched.

Fibromyalgia results in widespread pain and tenderness throughout the body. Generalized stiffness, fatigue, and muscle aches are reported.

osteomyelitis (infections of the bones of the spine), I s another skeletal causes of low back pain. Noninfectious inflammation of the spine (spondylitis) can cause stiffness and pain in the spine that is particularly worse in the morning.Tumors, possibly cancerous, can be a source of skeletal pain.

Inflammation of nerves from the spine can occur with infection of the nerves with the herpes zoster virus that causes shingles. This can occur in the thoracic area to cause upper back pain or in the lumbar area to cause low back pain.

Symptoms of back pain are as follows

Pain in the lower part of the back is the primary symptom of low back pain. The pain may progress down the front, side, or back of leg, or it may be confined to the low back. The pain may become worse with activity. Occasionally, the pain may be worse at night or with prolonged sitting such as on a long car trip. A person may have numbness or weakness in the part of the leg that receives its nerve supply from a compressed nerve. This can cause an inability to plantar flex the foot. This means person would be unable to stand on your toes or bring your foot downward. This occurs when the first sacral nerve is compressed or injured. Another example would be the inability to raise your big toe upward. This results when the fifth lumbar nerve is compromised.

The prevention of back pain is, itself, somewhat controversial. It has long been thought that exercise and an all-around healthy lifestyle would prevent back pain. This is not necessarily true. In fact, several studies have found that the wrong type of exercise such as high-impact activities may increase the chance of suffering back pain. Nonetheless, exercise is important for overall health and should not be avoided.

  • Low-impact activities such as swimming, walking, and bicycling can increase overall fitness without straining the low back.
  • Abdominal crunches, when performed properly, strengthen abdominal muscles and may decrease the tendency to suffer back pain.
  • Although not useful to treat back pain, stretching exercises are helpful in alleviating tight back muscles.
  • The pelvic tilt also helps alleviate tight back muscles.
Leg pain-
  • Patients with poorly controlled diabetes may develop diabetic neuropathy, in which some of the symptoms may include pain and loss of sensation in the feet.
  • Diabetes is also one of the risk factors for peripheral vascular disease, which may cause narrowing of blood vessels in the legs. This may cause exercise-induced pain when muscles don't get an adequate blood supply to meet their metabolic needs.
  • An injured muscle will cause pain because of inflammation and swelling, but it may also affect the balance of muscles surrounding a joint. If this imbalance persists, the joint may start to hurt because of chronic stresse placed upon it.

Leg pain occurs due to several facts, some of such are as follows,


Trauma is the most obvious cause of leg pain. Falling, twisting of leg injuries can damage bones, muscles, and joints or a combination of all three. Pain from an injury to the back can inflame the sciatic nerve and cause pain that radiates down the leg.

Fractures: The terms fracture, broken, and cracked all mean the same thing when referring to a bone. It means that the natural structure of the bone has been compromised. The most common symptom is pain which arises from the nerve endings located in the lining of the bone itself, called the periosteum (surrounding bone). As well, the muscles surrounding the bone go into spasm and intensify the pain.

Sprains and strains: A ligament injury is called a sprain and occurs when the ligament fibers are stretched, or partially or completely torn. Muscles and tendons can also be stretched or torn, causing a strain. Both sprains and strains result in swelling and inflammation that causes pain. Bleeding: Injuries can also cause bleeding into tissues and joints. Since blood, like any fluid, cannot be compressed, the swelling causes significant amount of pain as the pressure increases.

Non-traumatic Leg Pain

There are numerous causes of non-traumatic leg pain, and there is no single way of classifying all of these causes, decided upon a diagnosis. Sometimes it can help to classify the potential causes based upon which part of the leg it hurts, whether the pain is in one leg or both, whether it is related to activity or occurs at rest, and whether underlying medical conditions exist that can precipitate leg pain.

Pain in only one leg would tend to be due to local problems and not necessarily due to a systemic (involving the entire body) illness. The presumption would be that such an illness would affect both legs. This is not necessarily always true, since gout (the body's inability to process uric acid) often attacks only one joint during an acute flare.

Peripheral artery disease: Pain in one leg may be due to peripheral artery disease, a decrease in arterial blood supply due to narrowing of blood vessels to the leg. Often the pain comes with activity, since walking requires more oxygen for the muscles and if the arteries are narrow and can't supply that need, the muscles begin to hurt. Blood vessels can be narrowed at any level, from the aorta (the large blood vessel that leaves the heart), to any of the branch arteries. Depending upon the level of narrowing and the particular muscles involved, the areas of perceived pain may be different.

Leg pain from peripheral artery disease that occurs with walking is called claudication. Since peripheral artery disease usually affects many blood vessels, both legs may be affected. The blood supply may decrease to the point at which pain occurs at rest, even without exercise. Poor blood supply to the legs may also compromise the integrity of the skin and may allow infection to occur.

Blood clot: A blood clot can completely obstruct one of the arteries to the leg and cause the acute onset of pain because the blood supply has been completely cut off. Aside from pain, the leg becomes cool and pale. While there are many potential sources of a blood clot, one common place to look is the heart. If the atrial fibrillation is present, there is the potential that small clots can form on the lining of the heart and it breaks the path of arteries, obstructing blood flow at points distant from the heart. Aside from the leg, the obstruction may occur in one of the blood vessels leading to the brain, causing a stroke.

Brufen Website

About Pain:


Brufen contains ibuprofen, a non-steroidal anti-inflammatory (NSAID). Ibuprofen is considered to be a core medicine and finds itself placed in the World Health Organisation's Essential Drugs List as a minimum medical need in a basic health care system. Ibuprofen is used as a pain reliever in inflammatory conditions and also to reduce fever. The normal dose is 200 to 400 mg given three times daily. The duration of action is approximately 4-8 hours. In children the dose is 5-10 mg/kg divided into three doses.

Ibuprofen does not breakdown in solution and can thus be used topically in a gel form for superficial musculoskeletal injuries. The gastro-intestinal problems can thus be lessened when used topically.

Types of pain

Somatic or musculo-skeletal pain: This occurs in tissues such as skin, muscle, joints, bones, and ligaments. It is often sharp and well localized and aggravated by movement.

Best remedy is by paracetamol, opioids NSAIDs or any combinations of these.

Visceral pain is deep dull ache or sharp pain originating from the internal organs of the main body cavities. Often this is poorly localised, and cramping or colicky in nature. It frequently produces referred pain also can be difficult to diagnose. Best remedies ate the opioids.

Nerve Pain stems from within the nervous system itself. This can be peripheral or central depending on the location of the nerves involved. Frequent causes include nerve degeneration causes such as multiple sclerosis, stroke, brain haemorrhage, oxygen starvation, nerve pressure causes such as a trapped nerve, nerve inflammation causes such as during a torn or slipped disc, or nerve infection causes such as shingles and other viral infections. Besides pain other sensations changes may be may be present such as touch, vibration, hot and cold, tingling, numbness, and weakness. Also there may be referred pain along the nerve supply to the region which maybe lancinating, shooting, burning, and hypersensitive.

For nerve pain, the more successful pain relievers include anti-depressants, anti-convulsants, anti-arrhythmics. Topical capsaicin, may also be helpful. Paracetamol, NSAIDs and Opioids are of little value for nerve pain.

Sympathetic Pain is due to an over-active sympathetic nervous system and central / peripheral nervous system mechanisms. This occurs more commonly after fractures and soft tissue injuries of the arms and legs, and these injuries may lead to Complex Regional Pain Syndrome (CRPS).

This can present as extreme hypersensitivity in the skin around the injury and also peripherally in the limb (allodynia). Sweating and loss of temperature control in the area can also be a feature of this type of pain. At times, the sufferer refuses to use painful limb, causing secondary problems such as muscle wasting, joint contractures, and osteoporosis of the bones in the long run.

Anti-depressants, anti-convulsants, and anti-arrhythmics may be helpful. Vasodilators that lower blood pressure can also be combined with these drugs. Appropriate multi-modal medications, sympathetic nerve blocks, and intensive rehabilitation combining occupational and physiotherapy must all be made available as needed.

Rosenbaum T, Simon SA, Islas LD. Ion channels in analgesia research. Methods Mol Biol. 2010;617:223-36.

Several recent techniques have allowed us to pinpoint the receptors responsible for the detection of nociceptive stimuli. Among these receptors, ion channels play a fundamental role in the recognition and transduction of stimuli that can cause pain. During the last decade, compelling evidence has been gathered on the role of the TRPV1 channel in inflammatory and neuropathic states. Activation of TRPV1 in nociceptive neurons results in the release of neuropeptides and transmitters, leading to the generation of action potentials that will be sent to higher CNS areas, where they will often be perceived as pain. Its activation will also evoke the peripheral release of pro-inflammatory compounds that may sensitize other neurons to physical, thermal, or chemical stimuli. For these reasons, and because its continuous activation causes analgesia, TRPV1 is now considered a viable drug target for clinical use in the management of pain. Using the TRPV1 channel as an example, here we describe some basic biophysical approaches used to study the properties of ion channels involved in pain and in analgesia.

Harding G, Campbell J, Parsons S, Rahman A, Underwood M. British pain clinic practitioners' recognition and use of the bio-psychosocial pain management model for patients when physical interventions are ineffective or inappropriate: results of a qualitative study. BMC Musculoskelet Disord. 2010 Mar 18;11(1):51

ABSTRACT: BACKGROUND: To explore how chronic musculoskeletal pain is managed in multidisciplinary pain clinics for patients for whom physical interventions are inappropriate or ineffective.

METHODS: A qualitative study was undertaken using semi-structured interviews with twenty five members of the pain management team drawn from seven pain clinics and one pain management unit located across the UK.

RESULTS: All clinics reported using a multidisciplinary bio-psychosocial model. However the chronic pain management strategy actually focussed on psychological approaches in preference to physical approaches. These approaches were utilised by all practitioners irrespective of their discipline. Consideration of social elements such as access to social support networks to support patients in managing their chronic pain was conspicuously absent from the approaches used.

CONCLUSIONS: Pain clinic practitioners readily embraced cognitive/behavioural based management strategies but relatively little consideration to the impact social factors played in managing chronic pain was reported. Consequently multidisciplinary pain clinics espousing a bio-psychosocial model of pain management may not be achieving their maximum potential.

Narouze SN. Ultrasound-guided interventional procedures in pain management: Evidence-based medicine. Reg Anesth Pain Med. 2010 Mar-Apr;35(2 Suppl):S55-8.

Recently, there has been a growing interest in the application of ultrasonography in pain medicine because ultrasound provides direct visualization of various soft tissues and real-time needle advancement and avoids exposing the health care provider and the patient to the risks of radiation. The machine itself is more affordable and transferrable than a fluoroscopy, computed tomography scan, or magnetic resonance imaging machine. These factors make ultrasonography an attractive adjunct to other imaging modalities in interventional pain management especially when those modalities are not available or feasible.The present article reviews the existing evidence that evaluates the role of ultrasonography in spine interventional procedures in pain management.

Huber G, Garg U. Quantitation of ibuprofen in blood using gas chromatography-mass spectrometry (GC-MS). Methods Mol Biol. 2010;603:289-96.

Ibuprofen is a non-narcotic, non-steroidal anti-inflammatory drug used for the treatment of pain, fever, and inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It is also used for induction of closure of patent ductus arteriosus (PDA) in neonates.

Although the exact mechanism of action of ibuprofen is not known, it is believed to mediate its therapeutic effects through the inhibition of cyclooxygenase and subsequently by the inhibition of prostacyclin production.

Risser A, Donovan D, Heintzman J, Page T. NSAID prescribing precautions. Am Fam Physician. 2009 Dec 15;80(12):1371-8.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used, but have risks associated with their use, including significant upper gastrointestinal tract bleeding. Older persons, persons taking anticoagulants, and persons with a history of upper gastrointestinal tract bleeding associated with NSAIDs are at especially high risk. Although aspirin is cardioprotective, other NSAIDs can worsen congestive heart failure, can increase blood pressure, and are related to adverse cardiovascular events, such as myocardial infarction and ischemia. Cyclooxygenase-2 inhibitors have been associated with increased risk of myocardial infarction; however, the only cyclooxygenase-2 inhibitor still available in the United States, celecoxib, seems to be safer in this regard. Hepatic damage from NSAIDs is rare, but these medications should not be used in persons with cirrhotic liver diseases because bleeding problems and renal failure are more likely. Care should be used when prescribing NSAIDs in persons taking anticoagulants and in those with platelet dysfunction, as well as immediately before surgery. Potential central nervous system effects include aseptic meningitis, psychosis, and tinnitus. Asthma may be induced or exacerbated by NSAIDs. Although most NSAIDs are likely safe in pregnancy, they should be avoided in the last six to eight weeks of pregnancy to prevent prolonged gestation from inhibition of prostaglandin synthesis, premature closure of the ductus arteriosus, and maternal and fetal complications from antiplatelet activity. Ibuprofen, indomethacin, and naproxen are safe in breastfeeding women. Care should be taken to prevent accidental NSAID overdose in children by educating parents about correct dosing and storage in childproof containers.

Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology. 2009 Dec;17(6):275-342.

OBJECTIVES: This review attempts to bring together information from a large number of recent studies on the clinical uses, safety and pharmacological properties of ibuprofen. Ibuprofen is widely used in many countries for the relief of symptoms of pain, inflammation and fever. The evidence for modes of action of ibuprofen are considered in relation to its actions in controlling inflammation, pain and fever, as well as the adverse effects of the drug.

SUMMARY OF OUTCOMES: At low doses (800-1,200 mg day(-1)) which in many countries are approved for non-prescription (over-the-counter) sale ibuprofen has a good safety profile comparable with paracetamol. Its analgesic activity is linked to its anti-inflammatory effects and is related to reduction in the ex vivo production in blood of cyclo-oxygenase (COX)-1 and COX-2 derived prostanoids. Higher prescription doses (circa 1,800-2,400 mg day(-1)) are employed long-term for the treatment of rheumatic and other more severe musculo-skeletal conditions. Recent evidence from large-scale clinical trials with the newer coxibs, where ibuprofen was as a comparator, have confirmed earlier studies which have shown that ibuprofen has comparable therapeutic benefits with coxibs and other NSAIDs. For long-term usage (6+ months) there are greater numbers of drop-outs due to reduced effectiveness of therapy, a feature which is common with NSAIDs. Spontaneous reports of adverse events and adverse drug reactions (ADRs) in clinical trails from long-term coxib comparator studies, as well as in epidemiological studies, shows that ibuprofen has relatively low risks for gastro-intestinal (GI), hepato-renal and other, rarer, ADRs compared with other NSAIDs and coxibs. A slightly higher risk of cardiovascular (CV) events has been reported in some, but not all studies, but the risks are in general lower than with some coxibs and diclofenac. The possibility that ibuprofen may interfere with the anti-platelet effects of aspirin, though arguably of low grade or significance, has given rise to caution on its use in patients that are at risk for CV conditions that take aspirin for preventing these conditions. Paediatric use of ibuprofen is reviewed and the main results are that the drug is relatively safe and effective as a treatment of acute pain and fever. It is probably more effective than paracetamol as an antipyretic.

CONCLUSIONS: This assessment of the safety and benefits of ibuprofen can be summarized thus: (1) Ibuprofen at OTC doses has low possibilities of serious GI events, and little prospect of developing renal and associated CV events. Ibuprofen OTC does not represent a risk for developing liver injury especially the irreversible liver damage observed with paracetamol and the occasional liver reactions from aspirin. (2) The pharmacokinetic properties of ibuprofen, especially the short plasma half-life of elimination, lack of development of pathologically related metabolites (e.g. covalent modification of liver proteins by the quinine-imine metabolite of paracetamol or irreversible acetylation of biomolecules by aspirin) are support for the view that these pharmacokinetic and notably metabolic effects of ibuprofen favour its low toxic potential. (3) The multiple actions of ibuprofen in controlling inflammation combine with moderate inhibition of COX-1 and COX-2 and low residence time of the drug in the body may account for the low GI, CV and renal risks from ibuprofen, especially at OTC doses.

Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: A meta-analysis. Neurology. 2010 Mar 23;74(12):995-1002.

BACKGROUND/ OBJECTIVE: Anti-inflammatory drugs may prevent Parkinson disease (PD) by inhibiting a putative underlying neuroinflammatory process. We tested the hypothesis that anti-inflammatory drugs reduce PD incidence and that there are differential effects by type of anti-inflammatory, duration of use, or intensity of use.

METHODS: MEDLINE and EMBASE were searched for studies that reported risk of PD associated with anti-inflammatory medications. Random-effects meta-analyses were used to pool results across studies for each type of anti-inflammatory drug. Stratified meta-analyses were used to assess duration- and intensity-response.

RESULTS: Seven studies were identified that met the inclusion criteria, all of which reported associations between nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and PD, 6 of which reported on aspirin, and 2 of which reported on acetaminophen. Overall, a 15% reduction in PD incidence was observed among users of nonaspirin NSAIDS (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.94), with a similar effect observed for ibuprofen use. The protective effect of nonaspirin NSAIDs was more pronounced among regular users (RR 0.71, 95% CI 0.58-0.89) and long-term users (RR 0.79, 95% CI 0.59-1.07). No protective effect was observed for aspirin (RR 1.08, 95% CI 0.92-1.27) or acetaminophen (RR 1.06, 95% CI 0.87-1.30). Sensitivity analyses found results to be robust.

CONCLUSIONS: There may be a protective effect of nonaspirin nonsteroidal anti-inflammatory drug use on risk of Parkinson disease (PD) consistent with a possible neuroinflammatory pathway in PD pathogenesis.

Yong SL, Coulthard P. Pain after surgery: Can protective analgesia reduce pain? A randomised clinical trial. Int J Surg. 2010 Mar 16.

AIM: To improve the patients postoperative pain experience using protective analgesia for patients undergoing third molar surgery under day case general anaesthesia.

MATERIAL AND METHODS: Patients were randomly allocated to a protective analgesia (1.6g modified release ibuprofen) or conventional analgesia (400mg conventional ibuprofen) orally 2 hours preoperatively. Surgical model was third molar surgery. Postoperative outcomes of interest were pain intensity at 30 minutes, 1, 6, 24 and 48 hours. The time to rescue analgesia, overall assessment of pain control, safety and tolerability profiles were also recorded.

RESULTS: 122 patients entered the study providing 98 evaluable patients for analysis. Patients in the protective analgesia group reported more pain than those in the conventional group at 30 minutes, 1, 6 and 48 hours following surgery, although this difference was only statistically significant at the 30 minutes time point. 62.2% of patients required rescue analgesia within 6 hours after surgery. The median time for patients who had to take rescue analgesia was 3.1 hours. Patients in the protective analgesia group reported a longer time to rescue analgesia compared with those in conventional analgesia group. Overall, 91.7% of patients were at least satisfied with their pain control.

CONCLUSION: There was no difference in the protective analgesia group compared with conventional analgesia group in improving postoperative pain experience. A different protective analgesia regime may be necessary, which employs a more aggressive and multimodal strategy for postoperative pain management.

Papantoniou VJ, Sotiropoulou EK, Valsamaki PN, Tsaroucha AG, Sotiropoulou MG, Ptohis ND, Stipsanelli AJ, Dimitrakakis KE, Marinopoulos SG, Tsiouris ST, Antsaklis AJ. Reduced uptake of the proliferation-seeking radiotracer technetium-99m-labelled pentavalent dimercaptosuccinic acid in a 47-year-old woman with severe breast epithelial hyperplasia taking ibuprofen: a case report. J Med Case Reports. 2010 Mar 17;4(1):89.

INTRODUCTION: Recent studies have reported a risk reduction in the progression of benign breast disease to breast carcinoma through COX-2 pathways. CASE PRESENTATION: We present a case of severe epithelial hyperplasia in a 47-year-old woman with increased breast density submitted to scintimammography by the proliferation-imaging tracer Technetium-99m-labelled pentavalent dimercaptosuccinic acid, before and after oral ibuprofen treatment for 4 weeks. The radiotracer uptake after ibuprofen intake was significantly reduced, both visually and by semi-quantitative analysis, based on calculation of lesion-to-background ratios.

CONCLUSION: In proliferating breast lesions, scintigraphically displayed reduction in Technetium-99m-labelled pentavalent dimercaptosuccinic acid uptake may indicate inhibition by ibuprofen in the pathway of malignant epithelial cell transformation.

Gonzlez EL, Patrignani P, Tacconelli S, Rodrguez LA. Variability of risk of upper gastrointestinal bleeding among nonsteroidal anti-inflammatory drugs. Arthritis Rheum. 2010 Feb 22.

OBJECTIVES:: Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) increase the risk of gastrointestinal bleeding/perforation (UGIB) but the magnitude of this effect for coxibs in the general population and the degree of variability across individual NSAIDs is still debated.

METHODS:: We conducted a systematic review of observational studies on NSAIDs and UGIB published between 2000 and 2008. We calculated pooled relative risk(RR) estimates of UGIB for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of UGIB.

RESULTS:: The RR of UGIB for tNSAIDs was 4.50(3.82-5.31) and for coxibs 1.88(0.96-3.71). Lower RRs than the overall NSAID one were observed for ibuprofen 2.6(2.17-3.33), rofecoxib 2.12(1.59-2.84), aceclofenac 1.44(0.65-3.2) and celecoxib 1.42(0.85-2.37) while higher RRs were for ketorolac 14.54(5.87-36.04) and piroxicam 9.94(5.99-16.50). Estimates of RR were 5.63(3.83-8.28) for naproxen, 5.57(3.94-7.87) for ketoprofen, 5.40(4.16-7.00) for indomethacin, 4.15(2.59-6.64) for meloxicam and 3.98(3.36-4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of UGIB associated with individual NSAIDs(r(2)=0.34, P=0.058) but a profound and coincident inhibition(>80%) of both COX-isozymes was associated with higher risk. NSAIDs with long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life.

CONCLUSIONS:: The risk of UGIB varied between individual NSAIDs at the doses commonly used in the general population. Drugs with long half-life or slow-release formulation and/or associated with profound and coincident inhibition of both COX-isozymes were associated with a greater risk of UGIB.

Pierce CA, Voss B. Efficacy and safety of Ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother. 2010 Mar;44(3):489-506.

OBJECTIVE: To evaluate the analgesic and antipyretic efficacy and safety of ibuprofen compared to acetaminophen in children and adults.

DATA SOURCES: Literature searches were performed using PubMed/MEDLINE (through August 2009) and EMBASE (through January 2008) and were restricted to the English language. In PubMed/MEDLINE, search terms used were ibuprofen, acetaminophen, paracetamol, clinical trials, and randomized controlled trials. EMBASE search terms included ibuprofen and acetaminophen, restricted to human and clinical trials.

STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Multiple review articles were studied for any pertinent references and this yielded additional articles. Only articles that directly compared ibuprofen and acetaminophen were eligible for this review.

DATA SYNTHESIS: Eighty-five studies that directly compared ibuprofen to acetaminophen were identified; 54 contained analgesic efficacy data, 35 contained antipyretic/temperature reduction data, and 66 contained safety data (some articles contained more than 1 type of data). Qualitative review of the literature revealed that, for the most part, ibuprofen was more efficacious than acetaminophen for the treatment of pain and fever in both pediatric and adult populations, and that these 2 drugs were equally safe. Meta-analyses on the subset of randomized clinical trial articles that reported sufficient quantitative information to calculate either an odds ratio (adverse event [AE]) or standardized mean difference (pain and fever) confirmed the qualitative results for adult (standardized mean difference [SMD] 0.69; 95% CI 0.57 to 0.81) and pediatric (SMD 0.28; 95% CI 0.10 to 0.46) pain at 2 hours postdose and pediatric fever (SMD 0.26; 95% CI 0.10 to 0.41) at 4 hours postdose. Conclusions regarding adult fever/temperature reduction could not be made due to a lack of evaluable data. The combined odds ratio for the proportion of adult subjects experiencing at least 1 AE slightly favored ibuprofen; however, the difference was not statistically significant (1.12; 95% CI 1.00 to 1.25). No significant difference between drugs in AE incidence was found for pediatric patients (0.82; 95% CI 0.60 to 1.12).

CONCLUSIONS: Ibuprofen is as or more efficacious than acetaminophen for the treatment of pain and fever in adult and pediatric populations and is equally safe.

Katakam LI, Cotten CM, Goldberg RN, Dang CN, Smith PB. Safety and Effectiveness of Indomethacin versus Ibuprofen for Treatment of Patent Ductus Arteriosus. Am J Perinatol..

We compared the rates of medical closure of patent ductus arteriosus (PDA) and complications (renal dysfunction, necrotizing enterocolitis, spontaneous intestinal perforation, and intraventricular hemorrhage) between infants treated with indomethacin and infants treated with ibuprofen.

We performed a retrospective comparative cohort study of infants treated with indomethacin or ibuprofen for symptomatic PDA at Duke University Medical Center between November 2005 and November 2007.

We identified 65 infants who received indomethacin and 57 who received ibuprofen. The rate of survival without surgical ductal ligation was 62% (40/65) in the indomethacin group and 58% (33/57) in the ibuprofen group ( P = 0.71). The rate of the composite of complications (death, necrotizing enterocolitis, or intestinal perforation) was 40% (26/65) in the indomethacin group and 32% (18/57) in the ibuprofen group ( P = 0.35). There was no significant difference between groups in elevation of serum creatinine during treatment.

In clinical practice, ibuprofen appears to be as effective as indomethacin for closure of patent ductus arteriosus with similar complication rates. The decision to use one agent over the other should be based on dose schedule preference and the currently published clinical trials until more safety and effectiveness data are available.

Linder N, Bello R, Hernandez A, Rosen C, Birk E, Sirota L, Pushkov Y, Klinger G. Treatment of Patent Ductus Arteriosus: Indomethacin or Ibuprofen? Am J Perinatol..

We compared ibuprofen and indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants. A retrospective comparative study was conducted at a pediatric tertiary center in preterm infants diagnosed with PDA. Infants born from January 2000 to June 2003 were treated with indomethacin, whereas infants born from July 2003 to November 2005 were treated with ibuprofen. The two treatment groups were compared. Demographic data and clinical, laboratory, and outcome data were collected from the medical files. Seventy-three infants were included in the ibuprofen group and 46 in the indomethacin group. No significant difference in efficacy was found between indomethacin and ibuprofen.

Compared with ibuprofen, indomethacin treatment was associated with significantly higher mean creatinine levels and a higher percent of infants with creatinine >1.2 mg/dL, hyponatremia <120 mmol/L, and platelet level <100,000 platelets/mL (3). There were no significant differences in bilirubin levels, incidence and grade of intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, rate of surgical duct ligation, sepsis, length of hospital stay, or mortality. Indomethacin and ibuprofen are equally effective for PDA closure in premature infants. Treatment with ibuprofen is safer, decreasing the risk of renal failure, thrombocytopenia, and hyponatremia.

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