Drugs Expert

Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months. Others apply acute to pain that lasts less than 30 days, chronic to pain of more than six months duration, and subacute to pain that lasts from one to six months. A popular alternative definition of chronic pain, involving no arbitrarily fixed durations is “pain that extends beyond the expected period of healing.”

What causes chronic pain?

The cause of chronic pain is not always clear. It may occur because brain chemicals that usually stop pain after you get better from an illness or injury are not working right. Or damaged nerves can cause the pain. Chronic pain can also occur without a known cause.

What are the symptoms?

The symptoms of chronic pain include:

• Mild to severe pain that does not go away
• Pain that may be described as shooting, burning, aching, or electrical
• Feeling of discomfort, soreness, tightness, or stiffness

Pain is not a symptom that exists alone. Other problems associated with pain include:

• Fatigue
• Sleeplessness
• Withdrawal from activity and increased need to rest
• Weakened immune system
• Changes in mood including hopelessness, fear, depression, irritability, anxiety, and stress
• Disability

What other problems can chronic pain cause?

If you have pain for a long time, it can make you feel very tired and may lead to depression. It can get in the way of your usual social and physical activities. You may have so much pain that you can’t go to work or school. The emotional upset may make your pain worse. Your body’s defense system (immune system) may get weak, leading to lots of infections and illnesses.

Types of chronic pain

Hundreds of pain syndromes or disorders make up the spectrum of pain. There are the most benign, fleeting sensations of pain, such as a pin prick. There is the pain of childbirth, the pain of a heart attack, and the pain that sometimes follows amputation of a limb. There is also pain accompanying cancer and the pain that follows severe trauma, such as that associated with head and spinal cord injuries.

• General somatic pain (pain from the outer body)
  • Pains from your skin and muscles are easily localized by the brain because these pains are common. You have experienced general somatic pain since childhood when you have fallen or been hit by a person or an object. Normally, somatic pain gets better in a few days.
  • Some people develop pain that never goes away. Fibromyalgia and chronic back pain are in this category.
  • General somatic pain is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin) or naproxen (Naprosyn) or with acetaminophen (Tylenol). Sometimes, opioids, such as morphine, may be needed.
• Visceral pain (pain from the internal organs)
  • Pain in your internal organs is more difficult for you to pinpoint because your brain doesn’t get much experience feeling pain from internal organs. The connections from pain sensors in your internal organs to your brain are less sophisticated than the nerve connections from your outer body.
  • You have experienced some visceral pains. Pain from acid indigestion or constipation is easy to recognize. These pains are easily treated and get better quickly either on their own or with treatment using nonprescription medicines.
  • But the pain from chronic pancreatitis (an inflammation of the pancreas) or chronic active hepatitis (an inflammation of the liver) can last a long time and be difficult to treat.
  • Visceral pain from gallstones or appendicitis, for example, can be treated with surgery. Other visceral pains can be treated with various non-opioid pain medications. Sometimes opioids may be needed.
• Bone pain
  • Pain in the bones from a bruise or a fracture is temporary. Pain from bone cancer, osteoporosis (softening of the bones that often appears in older people), osteomyelitis (an infection in a bone), or arthritis (inflammation of the joints) can last a long time.
  • Bone pain is gnawing and throbbing. If you suffer from this, you may need long-term pain treatment. Bone pain may be treated with hormonal therapy or with bisphosphonates, such as alendronate (Fosamax), which strengthen the bones. Often, the NSAIDs (such as ibuprofen) are used. Sometimes opioids are needed.
• Muscle spasm (muscle cramps)
  • Muscle spasm, like a charley horse, can cause severe pain especially in the back. Pain medication alone may not be able to cure the pain. Muscle relaxants such as cyclobenzaprine (Flexeril) or baclofen (Lioresal) may be needed to relax the muscles.
• Peripheral neuropathy (pain arising in the nerves leading from the head, face, trunk, or extremities to the spinal cord)
  • In a sense, all pain comes from nerves because nerves transmit painful impulses to the brain. But some painful impulses do not arise from the nerve endings that normally sense injury or illness. Some painful impulses come from irritation to the nerve along its length instead of at the nerve ending.
  • Sciatica, for example, is caused by pinching of the sciatic nerve, which goes from the leg to the spine. The pinching often takes place near the lower part of the spine, but the brain “thinks” the pain came from the nerve endings in the leg because the sciatic nerve usually transmits feelings from the leg.
  • Other examples of illnesses that cause peripheral neuropathy or “nerve pain” are ruptured discs in the spine, which pinch nerves, cancers that grow into nerves and cause irritation, or infections, such as shingles, which can cause irritation to nerves.
  • Common diseases that often cause peripheral neuropathy are diabetes and AIDS.
  • Nerve pain can feel like a painful “pins and needles” sensation. This kind of nerve pain can be treated with tricyclic antidepressants. Other, more severe nerve pain can be described as a sharp, stabbing, electric feeling. Anticonvulsants (medicines that treat seizures) are used for this kind of nerve pain.
  • Some nerve pain is due to loss of a limb. The arm or leg that has been lost feels like it’s still present, and hurts severely. This kind of nerve pain, called deafferentation, or “phantom limb pain,” can be treated with clonidine (Catapres) (a blood pressure medicine that also relieves nerve pain).
  • Herpes zoster (shingles) causes an infection of the nerve endings and of the skin near the nerve endings. Local application of capsaicin (Zostrix), an over-the-counter pain medication in the form of an ointment, is sometimes helpful for this. In addition, opioids may be needed.
• Circulatory problems
  • Poor circulation is often a cause of chronic pain. Poor circulation is usually caused by tobacco use, diabetes, or various autoimmune diseases (diseases where the body makes antibodies that fight against itself) such as lupus or rheumatoid arthritis.
  • Partial blockage of arteries by fatty deposits called plaques is also a common cause of poor circulation. The reason for the pain of poor circulation is that the part of the body that does not get good blood circulation becomes short of oxygen and nourishment. The lack of oxygen and nutrition causes damage to that part of the body, and the damage causes pain.
  • Pain from poor circulation may be treated by surgery to bypass the clogged arteries with artificial arteries in order to improve the blood circulation. Sometimes this is not possible, and blood thinners or opioids may be needed to control the pain.
  • Another common cause of poor circulation is reflex sympathetic dystrophy (RSD). This is a problem of both circulation and nerve transmission because painful nerve transmissions cause the blood vessels to get narrower. The narrowing prevents enough oxygen and nourishment from getting to the part of the body that is affected. RSD can sometimes be treated with a surgical sympathectomy, an operation to stop the nerve impulses from causing a narrowing of the blood vessels. Often, non-opioid medication, either with or without surgery, is needed. Sometimes opioids are needed.
• Headaches
  • Headaches can be caused by many illnesses. There are several types of headaches, including migraine, tension, and cluster headaches. Headaches can also result from sinusitis, trigeminal neuralgia, giant cell arteritis, or brain tumors. The treatment of the various kinds of headaches varies depending on the kind of headache and the severity of the pain. Often, non-opioid medicines are used. But, in some cases, opioid therapy is needed.
  • Migraines are often on one side of the head. They can be associated with nausea and vomiting, photophobia (light hurting the eyes), phonophobia (sound hurting the ears), and scintillating scotomata (parallel lines that vibrate at the edges of objects, especially at the borders between light and dark places). Sometimes these auras appear before the headache starts and alert you that a migraine is coming. Migraine pain can vary in intensity from mild to severe. There are many specific medications for migraine. Sumatriptan (Imitrex) is particularly useful for some, but not all, migraine sufferers.
  • Cluster headaches come in groups, sometimes several times a day, lasting for days to weeks. Many cluster headaches are severely painful. Oxygen therapy may be helpful for some cluster headaches.
  • Sinusitis can cause facial pain and is frequently worse in the morning. Sinus pain may respond to antibiotic treatment along with decongestants. Sometimes sinus surgery is needed.
  • Trigeminal neuralgia is actually a peripheral neuropathy (nerve pain) that is severe. It occurs on one side of the head and face and has a “trigger point,” usually on the side of the face, which causes intense pain if it is touched. Anticonvulsants (antiseizure medicine) are often helpful for this type of pain.

How is chronic pain diagnosed?

There is no way to tell how much pain a person has. No test can measure the intensity of pain, no imaging device can show pain, and no instrument can locate pain precisely. Sometimes, as in the case of headaches, physicians find that the best aid to diagnosis is the patient’s own description of the type, duration, and location of pain. Defining pain as sharp or dull, constant or intermittent, burning or aching may give the best clues to the cause of pain. These descriptions are part of what is called the pain history, taken by the physician during the preliminary examination of a patient with pain.

Physicians, however, do have a number of technologies they use to find the cause of pain. Primarily these include:

• Electrodiagnostic procedures include electromyography (EMG), nerve conduction studies, and evoked potential (EP) studies. Information from EMG can help physicians tell precisely which muscles or nerves are affected by weakness or pain. Thin needles are inserted in muscles and a physician can see or listen to electrical signals displayed on an EMG machine. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock that stimulates the nerve that runs to that muscle. The second set of electrodes is used to make a recording of the nerve’s electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes-one set for stimulating a nerve (these electrodes are attached to a limb) and another set on the scalp for recording the speed of nerve signal transmission to the brain.

• Imaging, especially magnetic resonance imaging or MRI, provides physicians with pictures of the body’s structures and tissues. MRI uses magnetic fields and radio waves to differentiate between healthy and diseased tissue.

• A neurological examination in which the physician tests movement, reflexes, sensation, balance, and coordination.

• X-rays produce pictures of the body’s structures, such as bones and joints.

Methods of treatment

You can use home treatment for mild pain or pain that you have now and then. Exercising, getting enough sleep, and eating healthy foods may help reduce chronic pain. Using over-the-counter pain medicines such as acetaminophen, aspirin, or ibuprofen may also help. You may want to try complementary therapies such as massage and yoga.

Talk to your doctor if your pain does not go away or if it gets worse. You may need to try different treatments to find what works for you. Medicines you take by mouth, shots of numbing medicine,mnerve stimulation, and surgery are used for some types of chronic pain. It is important to make a clear treatment plan with your doctor. The best plan may include combining treatments.

The major classes

Paracetamol and NSAIDs

The exact mechanism of action of paracetamol/acetaminophen is uncertain, but it appears to be acting centrally. Aspirin and the other non-steroidal anti-inflammatory drugs () inhibit cyclooxygenases, leading to a decrease in prostaglandin production. This reduces pain and also inflammation (in contrast to paracetamol and the opioids).

Paracetamol has few side effects and is regarded as safe, although excessive doses can lead to fatal kidney and liver damage in the form of analgesic nephropathy and paracetamol hepatotoxicity, respectively. NSAIDs predispose to peptic ulcers, renal failure, allergic reactions, and occasionally hearing loss, and they can increase the risk of hemorrhage by affecting platelet function. The use of aspirin in children under 16 suffering from viral illness may contribute to Reye syndrome.

COX-2 inhibitors

These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least 2 different versions: COX1 and COX2. Research suggested that most of the adverse effects of NSAIDs were mediated by blocking the COX1 (constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible) enzyme. The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib and celecoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. However, post-launch data indicated increased risk of cardiac and cerebrovascular events with these drugs due to an increased likelihood of clotting in the blood due to a decrease in the production of protoglandin around the platelets causing less clotting factor to be released, and rofecoxib was subsequently withdrawn from the market. The role for this class of drug is debated.

Opiates and morphinomimetics

Morphine, the archetypal opioid, and various other substances (e.g. codeine, oxycodone, hydrocodone, dihydromorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system. Tramadol and buprenorphine are thought to be partial agonists of the opioid receptors. Tramadol is structurally closer to venlafaxine than to codeine and delivers analgesia by not only delivering “opiate-like” effects (through mild agonism of the mu receptor) but also by acting as a weak but fast-acting serotonin and norepinephrine reuptake inhibitor. Nevertheless, dosing of all opioids maybelimited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), seizures (Tramadol), but there is no dose ceiling in patients who tolerate this.

Opioids, while very effective analgesics, may have some unpleasant side-effects. Up to 1 in 3 patients starting morphine may experience nausea and vomiting (generally relieved by a short course of antiemetics). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives (lactulose, macrogol-containing or co-danthramer) are typically co-prescribed.

When used appropriately, opioids and similar narcotic analgesics are otherwise safe and effective, however risks such as addiction and the body becoming used to the drug (tolerance) can occur. The effect of tolerance means that drug dosing may have to be increased if for a chronic disease. In toxicity tolerant patients, there is no ceiling limit for the drug. However, though there is no upper limit, toxic doses are possible even if the body has become accustomed to higher doses.

Flupirtine

Flupirtine is a centrally acting K+ channel opener with weak NMDA antagonist properties. It is used in Europe for moderate to strong pain and migraine and its muscle relaxant properties. It has no anticholinergic properties and is believed be devoid of any activity on dopamine, serotonin or histamin receptors. It is not addictive and tolerance does not develop.

Specific agents

In patients with chronic or neuropathic pain, various other substances may have analgesic properties. Tricyclic antidepressants, especially amitriptyline, have been shown to improve pain in what appears to be a central manner. Nefopam is used in Europe for pain relief with concurrent opioids. The exact mechanism of carbamazepine, gabapentin and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with differing degrees of success. Anticonvulsants are most commonly used for neuropathic pain as their mechanism of action tends to decrease the firing of specific nerve systems.

Specific forms and uses

Combinations

Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers.

The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combatting pain at multiple sites of action—NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain—thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two be prescribed together.

Topical or systemic

Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen- or diclofenac-containing gel; capsaicin also is used topically. Lidocaine, an anesthetic, and steroids may be injected into painful joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for dental work and minor medical procedures.

Psychotropic agents

Tetrahydrocannabinol (THC) and some other cannabinoids, either from the Cannabis sativa plant or synthetic, have analgesic properties, although the use ofcannabisderivatives is currently illegal in many countries. A recent study finds that inhaled cannabis is effective in alleviating neuropathy and pain resulting from e.g. spinal injury and multiple sclerosis. Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α2-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues.

Atypical and/or adjuvant analgesics

Orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin, first-generation antidepressants and other drugs possessing anticholinergic and/or antispasmodic properties are used in many cases along with analgesics to potentiate centrally acting analgesics such as opioids when used against pain especially of neuropathic origin and to modulate the effects of many other types of analgesics by action in the parasympathetic nervous system. Dextromethorphan has been noted to slow the development of tolerance to opioids and exert additional analgesia by acting upon the NMDA receptors; some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action. High-alcohol liquor has been used in the past as an agent for dulling pain, due to the CNS depressant effects of ethyl alcohol, a notable example being the American Civil War. However, the ability of alcohol to “kill pain” may be inferior to many analgesics used today (e.g. morphine, codeine). As such, the idea of alcohol for analgesia is generally considered a primitive practice in virtually all industrialized countries today.

The use of adjuvant analgesics is an important and growing part of the pain-control field and new discoveries are made practically every year. Many of these drugs combat the side effects of opioid analgesics, an added bonus. For example, antihistamines including orphenadrine combat the release of histamine caused by many opioids, methylphenidate, caffeine, ephedrine, dextroamphetamine, and cocaine work against heavy sedation and may elevate mood in distressed patients as do the antidepressants. A well-accepted benefit of THC to chronic pain patients on opioids is its superior anti-nauseant action. Some think it would make more sense to use the synthetic THC capsule (trade name Marinol), which is administered orally. However, in patients suffering from nausea, the swallowing of the capsule itself may provoke vomiting. Likewise, the use of medicinal cannabis remains a debated issue.

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Prognosis

Chronic pain may cause other symptoms or conditions, including depression and anxiety. It may also contribute to decreased physical activity given the apprehension of exacerbating pain. Very little work has been done on the cognitive effects of chronic pain, with most of the publications focussing on the effects of cognition on pain but only 5% examining the effects of pain on cognition.

People with high-intensity chronic pain have significantly reduced ability to perform attention-demanding tasks. Pain appears to strongly capture the attention of people with chronic pain; tests assessing the ability to attend show poorer performance than pain-free people on all tests demanding attention. The exception is found with tasks that are highly demanding of attention, where performance between the two groups is equivalent. In experimental testing, two-thirds of individuals with chronic pain demonstrate clinically significant impairment of attention, independent of age, education, medication and sleep disruption. Individuals with the highest levels of pain showed greatest disruption of memory traces, suggesting that pain diminishes working memory.

Living with chronic pain can be hard. Counseling may help you cope. It can also help you deal with frustration, fear, anger, depression, and anxiety. Chronic pain often can be managed so that you can get on with your life and do your daily activities.