Pain Management

Inflammation and prostaglandins

Inflammation is a normal reaction to protect the body from harmful pathogens or irritants, such as chemicals, and to promote healing of damaged tissues. It is a complex process of cellular interactions of the immune system that is mediated by chemicals produced at the site of tissue damage, infection or trauma.

The process of inflammation includes the widening and increased permeability of small blood vessels, exudation of fluid into and migration of immune cells like macrophages and neutrophils into the tissues where damage, infection or irritation has occurred. The fluid causes swelling and the cells produce inflammatory chemicals like prostaglandins, interleukins and leukotrienes. These chemicals attract more inflammatory cells to help with wound healing and disposing of harmful pathogens but they also magnify the inflammatory response. In doing their job, some of these inflammatory mediators can also cause pain, swelling, fever and redness. If the inflammatory process continues beyond protecting and healing, it becomes chronic and can end up damaging normal tissues.

Inflammatory conditions

Inflammation is the cause of pain in a wide range of chronic and acute conditions, including:

• Inflammatory joint diseases like, rheumatoid arthritis an autoimmune disease, where the lining of the joint (synovium) becomes inflamed and the bone becomes eroded; osteoarthritis, a degenerative disease of the joints caused by wear and tear where the cartilage around the bone is worn away, most commonly in the hands, feet, hips and spine; ankylosing spondylitis, an autoimmune inflammatory disease that affects joints in the spine and pelvis and can cause fusion of the spine.


• Soft tissue injuries, such as sprains and strains that are due to trauma to the tendons, ligaments, muscles or joints.


• Soft tissue inflammation of synovial tissue that lines the joint surfaces and cavities, including bursae (fluid-filled sac between bones and tendons), tendons and ligaments surrounding joints.


• Menstrual pain (dysmenorrhea).


• Post-operative pain following surgery.

Nonsteroidal anti-inflammatory drugs (NSAID)

Nonsteroidal anti-inflammatory drugs (NSAID) inhibit cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins like PGE2, which have important functions throughout the body but are also potent inflammatory mediators and cause pain, swelling and other symptoms of inflammation. They are called nonsteroidal as corticosteroid drugs are also used to treat inflammation and these target a different enzyme in the pathway of prostaglandin synthesis.

There are two known COX enzymes, COX-1, COX-2 and there is also a variant of COX-1, known as COX-3, which is found mainly in the brain. COX-1 is present in most cells and plays an important role in many normal cell functions, including aggregation of blood platelets, which controls bleeding; protection of the stomach lining or mucosa by promoting cell growth; also in maintaining normal kidney function by regulating blood flow. COX-2 is only produced by inflammatory cells, and is induced during the inflammatory process, although it is also found in very small amounts in some tissues.

NSAID medications

NSAID medications include:

• Ibuprofen and diclofenac that inhibit both COX-1 and COX-2, and is the cause of the more serious side effects of non-specific COX inhibitors. These include gastric bleeding and ulcers due to the inhibition of prostaglandins that are protective of the gastric mucosa and have vasodilator (cause widening of blood vessels) action which helps maintain normal blood flow. Kidney damage is also a potentially serious side effect particularly in those with impaired kidney function and again this is due to the inhibition of protective prostaglandin production by blocking COX-1.


• Diclofenac that inhibits primarily COX-2 but also has some inhibitory effect on COX-1 and is therefore more specific as an anti-inflammatory.


• Meloxicam and celecoxib that are specific COX-2 inhibitors and have no inhibitory action against COX-1, which makes them more effective for pain and inflammation, without the gastrointestinal or kidney side effects associated with COX-1 inhibition.

What is migraine?

Migraine is a neurological disorder with symptoms that include an intense, throbbing and painful headache, often accompanied by an aura, which is the perception of visual disturbances that appear as flashing lights or zig-zag lines and are usually the first sign that a migraine headache is on its way. A migraine is also associated with extreme sensitivity to light, sound, touch and smell. Other symptoms are gastrointestinal effects including nausea, vomiting and delayed emptying of the stomach into the small intestine, which reduces absorption of medications and can explain why oral medications are not effective fast enough. A migraine attack can last between four and 72 hours.

For many years migraine headache was considered to be a vascular headache and the primary cause was thought to be entirely due to constriction followed by extreme dilatation or widening of blood vessels in the head, with leakage of inflammatory chemicals, which in turn irritate nearby sensory nerves causing pain. With new developments in neuroscience, the current thinking is that migraine headache is a neurological disorder involving abnormalities in nerve pathways and brain chemicals or neurotransmitters. It is also now thought that there are distinct genes related to migraines and that there is a genetic component to developing migraines due to the presence of abnormal genes that control certain areas of the brain.

There are many possible migraine triggers, including, stress, hunger, lack of sleep, dietary factors, and hormonal changes such as during the menstrual cycle.

Migraine treatments

Medications for treatment of migraine currently focus on the vascular basis of migraine headache to prevent blood vessel widening by targeting two different neurotransmitters (brain chemical that allow brain cells to communicate), serotonin and noradrenaline. These neurotransmitters act on specific receptors in the brain and control the stability of peripheral blood vessels in terms of dilation and constriction. Other medications are used for control of migraine symptoms by combining an analgesic and antiemetic.

Serotonin agonists

Serotonin is a brain chemical or neurotransmitter that is involved in control of mood, pain sensation, sexual behaviour, sleep, as well as dilation (widening) and constriction (narrowing) of blood vessels. Sumatriptan is a member of the group of drugs called tryptans and is a serotonin agonist that mimics the action of serotonin (also known as 5-hydroxytryptamine, or 5-HT). Sumatriptan acts specifically on the 5-HT1 receptor, which is a sub-type of the serotonin receptor that is found predominantly in the blood vessels of the brain, causing them to constrict or narrow. Sumatriptan is also thought to inhibit trigeminal nerve activity, relieving pain.

Treatment with sumatriptan should begin as soon as possible after symptoms begin and Injection is the fastest treatment for migraine relief, being effective within 10-15 minutes. A nasal spray is also available which delivers sumatriptan directly into the nasal passages where it is rapidly absorbed through the skin and is active within 15 minutes; this is particularly suitable if nausea and vomiting during a migraine attack make it difficult to take tablets. Sumatriptan is not fully absorbed so oral administration with tablets can take up to 30 minutes to relieve symptoms, although rapid release fast disintegration tablets are available to speed up absorption of sumatriptan. Sumatriptan does not prevent migraine attack and is not effective for other types of headache.

Alpha-agonists

Clonidine is an alpha-agonist that acts on alpha adrenergic receptors in the brain and central nervous system, which are usually stimulated by the neurotransmitter noradrenaline. Blood vessels in the brain have alpha adrenergic receptors and are responsive to adrenergic stimulation by the neurotransmitters adrenaline and noradrenaline. This stimulation causes the blood vessels to widen (vasodilation) or contract (vasoconstriction). Clonidine binds to alpha adrenergic receptors on peripheral blood vessels in the brain and this reduces their responsiveness to adrenergic stimuli and thereby controls the extreme dilatation that is thought to be associated with migraine headache.

Symptom relief

A combination of the analgesic paracetamol and the anti-emetic metoclopramide is used to help relieve symptoms of migraine, including pain, nausea, vomiting and gastric stasis, or delayed emptying of the stomach, which can slow down the absorption of migraine medication.

Paracetamol works by selectively inhibiting the enzyme cyclooxygenase 2 (COX-2) that is required for the production of prostaglandins, which are chemicals produced in response to inflammation and injury and can also sensitise nerve endings in the pain centres in the brain. Paracetamol blocks the production of pain-inducing prostaglandins, to relieve the pain associated with migraine headaches.

Metoclopramide is an antiemetic (prevents nausea and vomiting) and a gastrokinetic (stimulates gastrointestinal mobility). It acts as a dopamine antagonist by binding to dopamine receptors in specific areas in the brain where the vomiting reflex is stimulated and blocks the vomiting reflex. Metoclopramide also binds to dopamine receptors in the stomach, which mediates increased contraction of the stomach muscles so that the stomach empties faster and this reduces nausea and vomiting and increases the passage of the oral medication into the intestine for faster absorption.

What is muscle spasm?

Muscle spasm or spasticity is defined as involuntary muscle contraction due to increased muscle tone (hypertonicity) or muscle stiffness, so that the muscles undergo excessive contraction and are resistant to stretch, which is the relaxed state. It is usually associated with damage to the nerve pathways in the brain or spinal cord involved in control of muscle movement, abnormal nerve stimulation, or abnormal activity of the muscle itself. Another form of muscle spasm is clonus, which is painful reflex muscle spasm due to a series of spontaneous involuntary muscle contraction and relaxations.

Muscle spasms can be the result of certain disorders of the nervous system, including multiple sclerosis, motor neurone disease, cerebral palsy and meningitis; also tumours or inflammation of the spinal cord; or following stroke or injuries to the head or spine. Skeletal muscle spasm may be caused by a wide range of injuries, including, sprains, strains and fractures; also a prolapsed intervertebral disc or lumbago (lower back pain) can trigger muscle spasm. Other conditions associated with muscle spasm include fibrositis or fibromyalgia, which is chronic pain and stiffness in the muscles tendons and joints, non-articular rheumatism (affecting soft tissue such as tendonitis), acute torticollis, which is spasm and shortening of a muscle in the neck causing the head to become twisted. Spasticity can result in abnormal posture or gait, exaggerated deep tendon reflexes, increased pain and can affect overall quality of life.

Muscle relaxants

Muscle contraction and relaxation is part of the neuromuscular control system that results in coordinated movement. It is normally under control of the motor neurones that receive messages from the brain and spinal cord to instruct a specific skeletal muscle to contract or relax. Muscle relaxants used to help treat painful muscle spasm act directly at the level of neurotransmitter, which are chemicals that allow nerve cells to communicate and this reduces uncontrolled muscle contraction. Muscle spasm can be treated with muscle relaxant medications that act directly at the level of nerve impulse transmission but work by different mechanism of action.

Analgesic anticholinergic

Orphenadrine is a muscle relaxant that has several mechanisms of action, including analgesic and muscle relaxant properties. It is thought to have anticholinergic action, which means that it blocks the receptors for acetylcholine, a neurotransmitter that activates skeletal muscle contraction. Orphenadrine works at the level of the central and peripheral nervous system, to help control involuntary muscle spasm. The combination of analgesic and anticholinergic action helps relieve pain due to muscle spasm.

GABA analogues

Baclofen is an analog of gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system and regulates how nerve cells in the spinal cord respond to stimulation. Baclofen stimulates GABA receptors which in turn inhibits the release of excitatory neurotransmitters like glutamate and aspartate that regulate sensory and motor neurones. This action suppresses nerve stimulation of reflexes at the spinal level that cause Involuntary muscle spasm and reduces pain associated with muscle spasm. Baclofen, however, does not have any effect on Neuromuscular transmission, which is the stimulation of the muscle to contract by release of acetylcholine by peripheral nerve cells.

What is nerve pain

Nerve pain or neuropathic pain is caused by damage to or malfunction of the peripheral or central nervous system. The initial trigger may be an injury such as loss of a limb; exposure of nerves to chemotherapy; inflammation of a nerve due to infection, sensitisation of a nerve following injury, such as disc damage; post-herpetic neuralgia (shingles) caused by nerve damage, where virus travels along the nerve and causes sensitisation, nerve entrapment as in carpel tunnel syndrome or strangulation by scar tissue. Nerve pain is usually chronic and persists long after the initial injury has healed. The pain becomes a central nervous system problem and can be stimulated without any apparent injury, by sub-threshold pain stimuli or just by increased perception. The pain felt is described as electric shocks, stabbing or burning pain.

Treatments for nerve pain

Treatments for nerve pain are based on the understanding that this type of pain is due to loss of normal control within the central nervous system in a way that is comparable to epilepsy. This is why medications that interact directly with the brain are often used as first line therapy, including anticonvulsants; also muscle relaxants and antidepressants are used in some cases.

Anti-convulsants

Anticonvulsant drugs are used to treat nerve pain because they help control the bursts of electrical activity in the brain that cause nerve pain. They work by preventing the repetitive firing of nerve messages (electrical and chemical) acting through different mechanisms, including; blocking sodium channels that are involved in setting up a nerve signal, blocking calcium channels that respond to a nerve signal and trigger the release of neurotransmitters, adjusting the balance between inhibitory and excitatory neurotransmitters, or a combination of these mechanisms.

For the brain to function normally it is important to have a balance between excitatory and inhibitory neurotransmitters. Glutamate is the major excitatory neurotransmitter and interacts with receptors that have excitatory effects, which means that they increase the probability that the target cell will set up an action potential and trigger a nerve signal. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter and interacts with receptors that have inhibitory effects by failing to trigger a nerve signal and this has a calming effect on nerve cells. Anti-convulsants that are used for nerve pain include:

• Gabapentin, a GABA analogue that is thought to control neurotransmission via voltage-gated calcium channels, which reduces the propagation of excitatory nerve transmissions and calms excitatory nerve cells, reducing nerve pain intensity.


• Carbamazepine and topiramate block sodium channels in nerve cell membranes that control the flow of sodium ions into the nerve cell and triggers an electrical transmission. This reduces the neurone’s ability to send out continuous signals reducing nerve pain intensity.


• Sodium valproate that works by increasing the activity of the inhibitory neurotransmitter GABA; also by preventing the reuptake of GABA by the pre-synaptic nerve cell Sodium valproate acts as a nerve cell membrane stabiliser by blocking voltage-dependent sodium channels.

Treatments for Gout

Gout and gouty arthritis are caused by excess uric acid in the blood being deposited in joints as crystals and causing inflammation, with its associated pain and swelling. Medications used for treating gout prevent uric acid crystal being deposited in the joints, which reduces inflammation and include.

• Probenecid a uricosuric drug that works by acting directly on the kidneys to limit the amount of uric acid in the blood and reduce crystal formation. This allows the crystals already in the joints to dissolve and the pain and swelling to be reduced.


• Colchicine inhibits migration of inflammatory leucocytes and also inhibits phagocytosis (ingestion) of uric acid crystals thereby reducing the amount of inflammatory chemicals released, which helps break the inflammation cycle. Colchicine also inhibits uric acid crystal deposition, which need a low pH (acid conditions), by increasing the pH and reducing acidity.

Treatments for osteoarthritis

Osteoarthritis is a degenerative disease of the joints caused by wear and tear, where the cartilage around the bone is worn away, most commonly in the hands, feet, hips and spine.

Cartilage plays an important role in joints by cushioning the bones and protecting them from rubbing against each other. Aging and injury can cause rapid degeneration of the cartilage and also, with age, less is produced. Glucosamine and chondroitin are building blocks for the synthesis of cartilage by the body. Dietary supplements containing glucosamine and chondroitin contribute to the synthesis of cartilage and may help slow down the progression of osteoarthritis and help to relieve pain associated with osteoarthritis.

Treatments for haemorrhoids

Haemorrhoids are swollen blood vessels around the anus. A combination medication available as an ointment or as suppositories is used as a treatment for haemorrhoids. Cinchocaine is a local anaesthetic and analgesic that also relaxes spasm of the anal sphincter. Hydrocortisone is an anti-inflammatory low potency corticosteroid and together these medications numb the pain, reduce the swelling and relieve the irritation and itching associated with haemorrhoids.