Pain and analgesics

Published on 02/03/2015 by admin

Filed under Basic Science

Last modified 02/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 5 (1 votes)

This article have been viewed 5580 times

Michael C. Lee, Mark Abrahams

Pain and analgesics

Nociception

Pain alerts us to ongoing or potential tissue damage and the ability to sense pain is vital to our survival. The physiological process by which pain is perceived is known as nociception. While the neurobiology of nociception is complex, its appreciation provides a useful framework for understanding the way analgesics work (Fig. 18.2).

Our nervous system is alerted to actual or potential tissue injury by the activation of the peripheral terminals of highly specialised primary sensory neurones called nociceptors. Nociceptors have unmyelinated (C-fibre) or thinly myelinated (Aδ-fibre) axons. Their cell bodies lie in the dorsal root ganglia of the spinal cord or in the trigeminal ganglia. Different nociceptors encode discrete intensities and modalities of pain, depending upon their expression of ion-channel receptors. These receptors are transducers. They convert noxious stimuli into action potentials. Some of these transducers have been identified, including those that respond to heat (> 46°C), cold (< 10°C) and direct chemical irritants such as capsaicin.

Action potentials that result from the transduction of noxious stimuli are conducted along the axon of the sensory neurone into the spinal cord. Conduction of the action potentials in sensory neurones depends on voltage-gated sodium channels, including two that are predominately expressed in nociceptors; Nav1.7 and Nav1.8.

The central terminal of the nociceptor makes synaptic contact with dorsal horn neurones within the spinal cord. Glutamate, an amino acid, is the main excitatory neurotransmitter released at these synapses. Its release can be inhibited by ligands that act to activate receptors found on the central terminal of the nociceptors (pre-synaptic inhibition). These include the opioids, cannabinoids, γ-aminobutyric acid (GABA)-receptor ligands and the anticonvulsants, gabapentin and pregabalin. Opioids and GABA also influence the action of glutamate on the dorsal horn neurones. They act on post-synaptic receptors to open potassium or chloride channels. This results in hyperpolarisation of the neurone, which inhibits its activity.

Other neurotransmitters may also be released by the central terminal of the nociceptors. For example, substance P is released during high-intensity and repetitive noxious stimulation. It mediates slow excitatory post-synaptic potentials and results in a localised depolarisation that facilitates the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate. The end-result is a progressive increase in the output from dorsal horn neurones. This amplified output is thought to be responsible for the escalation of pain when the skin is repeatedly stimulated by noxious heat – a phenomenon known as wind-up.

Nociceptive output from the spinal cord is further modulated by descending inhibitory neurones that originate from supraspinal sites such as the periaqueductal gray or the rostral ventromedial medulla and terminate on nociceptive neurones in the spinal cord as well as on spinal inhibitory interneurones that store and release opioids. Stimulation of these brain regions, either electrically or chemically (e.g. opioids), produces analgesia in humans. Transmission through these inhibitory pathways is facilitated by monoamine neurotransmitters such as noradrenaline/norepinephrine and serotonin.

Finally, dorsal horn neurones send projections to supraspinal areas in the brainstem, hypothalamus, and thalamus and then, through relay neurones, to the cortex where the sensation of pain is perceived. The mechanism by which the cortex produces the conscious appreciation of pain is the focus of much research.

Classification of clinical pain

Rational pharmacological treatment of clinical pain depends on a number of factors, including the underlying cause and duration of pain, the patient’s general medical condition and prognosis. Clinical pain is generally divided into three broad categories; acute, chronic, and cancer-related.

Evaluation of pain

Achieving optimal pharmacological management of the patient’s pain will depend on the type and cause of pain, as well as the psychological and physical condition of the patient. A comprehensive evaluation of the pain is, therefore, essential if we are to treat the patient successfully and safely. Underlying organic pathology must be excluded unless an obvious cause of pain is apparent (e.g. after recent surgery or trauma). The presence of organic pathology should also be suspected if the patient’s pain presents in an unusual way, or is of a much greater magnitude than would normally be expected from the assumed pathology.

Once an organic explanation has been eliminated, additional tests are unhelpful. The illusory sense of progress such tests provide for both physician and patient may perpetuate maladaptive behaviour and impede the return to more normal function.

The evaluation of persistent pain should include pain location, quality, severity, duration, course, timing (including frequency of remissions and degree of fluctuation), exacerbating and relieving factors, and co-morbidities associated with the pain (with emphasis on psychological issues, depression, and anxiety). The efficacy and adverse effects of currently or previously used drugs and other treatments should also be determined.

If appropriate, the patient should be asked if litigation is ongoing or whether financial compensation for injury will be sought. A personal or family history of chronic pain can often give insight into the current problem. The patient’s level of function should be assessed in detail, focusing on family relationships (including sexual), social network, and employment or vocation. The interviewer should elicit how the patient’s pain affects the activities of normal living.

It is also important to determine what the pain means to the patient. In some patients, reporting pain may be more socially acceptable than reporting feelings of depression or anxiety. Pain and suffering should also be distinguished. In cancer patients, in particular, suffering may be due as much to loss of function and fear of impending death as to pain. The patient’s expression of pain represents more than the pathology intrinsic to the disease.

Thorough physical examination is essential, and can often help to identify underlying causes and to evaluate, further, the degree of functional impairment. A basic neurological examination may identify features associated with neuropathic pain including:

Non-opioid analgesics

NSAIDs (non-steroidal anti-inflammatory drugs)

Mechanism of analgesia

Endothelial damage produces an inflammatory response in tissues. Damaged cells release intracellular contents, such as adenosine triphosphate, hydrogen and potassium ions. Inflammatory cells recruited to the site of damage produce cytokines, chemokines and growth factors. A profound change to the chemical environment of the peripheral terminal of nociceptors occurs. Some factors act directly on the nociceptor terminal to activate it and produce pain, and others sensitise the terminal so that it becomes hypersensitive to subsequent stimuli. This process is known as peripheral sensitisation.

Prostanoid is a major sensitiser that is produced at the site of tissue injury. NSAIDs act by inhibiting cyclo-oxygenase, an enzyme involved in the production of prostanoid, as well as other prostaglandins. This enzyme has a number of isoforms, the most studied being cyclo-oxgenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). Their actions are inhibited by NSAIDs (see Ch. 16). Increased COX-2 production is induced by tissue injury and accounts for the efficacy of COX-2-specific inhibitor drugs (COXIBs). The inhibitory effect of NSAIDs on the production of other prostaglandins is responsible for the common side-effects of these drugs. Among other functions, the prostaglandins produced by cyclo-oxygenase act to protect the gastric mucosa, maintain normal blood flow in the kidney and preserve normal platelet function. Inhibition of prostaglandin production, therefore, can cause gastric irritation, damage to the kidney and an increased risk of bleeding.

Opioid analgesics

Opium (the dried juice of the seed head of the opium poppy) was used in prehistoric times. Modern medical practice still benefits from the use of its alkaloids, employing them as analgesics, tranquillisers, antitussives and in the treatment of diarrhoea.

The principal active ingredient in crude opium was isolated in 1806 by Friedrich Sertürner, who tested pure morphine on himself and three young men. He observed that the drug caused cerebral depression and relieved toothache, and named it after Morpheus, the Greek god of dreams. Opium contains many alkaloids, but the only important opiates (drugs derived from opium) are morphine (10%) and codeine. Papaverine is occasionally used as a vasodilator.

Opioid is a generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action.

Systemic effects of opioid analgesics

Central nervous system

Opioids reduce the intensity and unpleasantness of pain. Patients taking opioid analgesics often report less distress, even when they can still perceive pain. Sedation occurs frequently, particularly in the early stages of treatment, but often resolves although it can remain a problem, especially at higher doses, and is a common cause of drug discontinuation in the chronic pain population.

The sensitivity of the respiratory centre to hypercarbia and hypoxaemia is reduced by opioids. Hypoventilation, due to a reduction in respiratory rate and tidal volume, ensues. Cough is inhibited by a central action. Prolonged apnoea and respiratory obstruction can occur during sleep. These effects are more pronounced when the respiratory drive is impaired by disease, for example in chronic obstructive pulmonary disease, obstructive sleep apnoea and raised intracranial pressure.

Opioid-related respiratory depression is more common in patients being treated for acute pain than in patients established on long-term opioids. Respiratory depression in use relates to high blood opioid concentrations, for example with an inappropriately large dose that fails to account for differences in patient physiology (e.g. in hypovolaemic trauma or the elderly), or because the patient is unable to excrete the drug efficiently (as a consequence of renal impairment). Respiratory depression is unusual in patients established on long-term opioids due to the development of tolerance. Sudden changes to the patient’s physiological state (e.g. the development of acute renal failure) may produce increases in blood opioid concentration and precipitate toxic effects.

Nausea and vomiting commonly accompany opioids used for acute pain. The mechanism may be activation of opioid receptors within the chemoreceptor trigger zone within the medulla, although opioid effects on the gastrointestinal tract and vestibular function probably play a role. Antiemetics are effective.

Miosis occurs due to an excitatory effect on the parasympathetic nerve innervating the pupil. Pin-point pupils are characteristic of acute poisoning; at therapeutic doses the pupils are merely smaller than normal.

Cardiovascular system

Buy Membership for Basic Science Category to continue reading. Learn more here