Pain is an adaptive, but unpleasant, sensation and emotional experience which acts as an early warning to protect the body from tissue damage; it allows the body to prevent further injury. People experience pain as signals from the stimuli are sent to the brain for interpretation via nerve fibres. Maladaptive pain is when the pain is out of proportion to the damage done to the tissues. Pain tolerance is the intensity or duration of pain that a person can bear before taking action and it is different in everybody as it increases with age, modified emotions and mental state. There are seven different types of pain: nociceptive; acute; chronic; somatic; visceral; inflammatory; neuropathic.
Nociceptive pain is activated only by harmful stimuli acting on sensory receptors. Nociceptors (pain receptors) are nerve endings that respond to a variety of stimuli that have the potential to cause damage. Nociceptor Ad and C afferent stimuli into action potentials that are conducted to the dorsal horn in the spinal cord. A reflex response occurs, causing involuntary muscle contractions. Somatic pain is a type of nociceptive pain which includes pain in skin, tissue and muscles. Somatic pain produces a persistent aching sensation, for example a bone fracture. Another form of nociceptive pain is visceral pain, which is the result of nociceptors in the thoracic, pelvic or abdominal organs being activated by a stimulus. Visceral pain is sensitive to over stretching, inflammation and ischaemia but not effected by stimuli which promote common pain such as burns or cuts. Acute pain is a sudden, sharp, prickling pain which is carried across the A fibres but not felt in deep tissues. It has a short duration and resolves itself as the tissue heals for example, touching a hot stove or a paper cut. Chronic pain is more persistent and has a slower response rate than acute pain. Chronic pain tends to last months and is associated with underlying conditions such as arthritis. Impulses from stimuli are carried by C fibres and may be burning, intense or throbbing pain that can arise in skin, deep tissues and organs. Neuropathic pain is caused by primary lesion or dysfunctions within the nervous system. Signals are sent through peripheral fibres and central neurons. It can be associated with abnormal sensations within stimuli such as allodynia and dysesthesia. Neuropathic pain can be peripheral (diabetic neuropathy, PHN, TN, scar pain) or it can be central (post stroke). Another example is phantom limb pain, which is a continuous painful sensation felt from a limb that is no longer there. Neuropathic pain is perceived differently; it can be a stabbing pain or a chronic prickling, tinging or burning sensation. Inflammatory pain is a response to the noxious stimuli that are triggered during an inflammatory or immune response. People may feel stiffness, distress and potentially intense pain during inflammation. It is associated within the deep tissues. Some mediators directly activate nociceptors for pain and others work together to produce a response of the somatosensory nervous system.
Current methods to control pain which are often used include relaxation therapy, applications of heat or cold, massages, acupuncture, stress reduction, hypnosis and exercise. Opioid receptors are activated by endorphins, which are released by neurons. Opioid receptors can also be exogenously activated via alkaloid opiates, such as morphine. Opioid analgesics bind to neuroreceptors and block the pain messages from being passed from the body to the brain. By acting at these receptors, opiates are enormously potent pain killers however, they are highly addictive. The non-opioid drugs, such as paracetamol and ibuprofen (and other NSAIDs), are predominantly appropriate for pain in musculoskeletal conditions, whereas the opioid analgesics are more suitable for moderate to severe pain, in particular visceral pain. NSAIDs reduce the production of prostaglandins, which promote inflammation, pain and fever. Cyclooxygenase (COX1 + COX2) are enzymes which produce prostaglandins. COX1 inhibition prevents gastric ulcers, bleeding and acute renal failure. COX2 inhibition reduces inflammation, pain and fever. Opioids also have proven to work in nociceptive and cancer related neuropathic pain. Tramadol is a narcotic-like pain relief medication that works by modifying the pain signals which travel from nerves to the brain. Tramadol has numerous different targets within the nervous system which each contribute to pain relief and mood-changing properties. As well as tramadol, medications used to help diabetic nerve pain include reuptake inhibitors (lamotrigine), tricyclic antidepressants (desipramine) and anticonvulsants (carbamazepine).
Inhibitory effects antidepressants have for neuropathic pain appear quicker than their antidepressant effects. This suggests that the main mechanism of antidepressants that inhibit neuropathic pain increase the noradrenaline in the spinal cord. This then acts on the locus coreleus, therefore inhibiting pain. Dopamine and 5-HT also increase in the CNS which may also enhance the inhibitory effects of noradrenaline. Anticonvulsants are extremely effective in treating diabetic neuropathy as they inhibit sodium channels and block spontaneous neural discharges. Anticonvulsants acting at voltage gated calcium channels can also treat neuropathic pain. Pregabalin and gabapentin are both from GABA however they do not have an effect on the GABAergic system. The bind to voltage gated calcium channels within the CNS, which are located on presynaptic terminals, where they can control the release of neurotransmitters.
Future therapeutics can research the importance of genes in pain, as different pain tolerances may be linked to the individual’s pain genes. Insensitivity to pain is inherited as a mutation which includes a loss of function in voltage gated channels The gene which is affected is called SCN9A and is a voltage gated sodium channel, recessive gene. Over ten new alternatives to this gene have been discovered recently which cause channel-associated insensitivity or indifference to pain. Other variations of this gene cause excessive feelings of pain. The use of CRISPR technology to ‘edit genes’ and develop human gene therapies may be an early stage and the first to undergo human clinical trials. This could be used to treat patients who suffer from chronic pain.