Analgesia and relief of pain

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Chapter 32 Analgesia and relief of pain

Chapter contents

Analgesics 248
Principles behind analgesic drugs 250
Specific analgesics 250

Pain is a very necessary sensation as its purpose is to signal harm to an organism. It allows the organism to adapt to its surroundings so that it can remove itself from the sensation or in the case of humans actively resolve the problem by treatment.

All pain receptors are free nerve endings and are called nociceptors. These are part of the process that transmits the pain to the brain (the process of nociception). Various sensory receptors found throughout the body react to a variety of stimuli, such as hot, cold, pressure and chemical, all of which can give the patient the subjective experience of pain. Different types of neuron carry the pain signal to the central nervous system (CNS):

• First-order neurons: transmit pain impulses. There are two subtypes:

• rapidly conducting (12–30 m/s), myelinated A fibres
• slow conducting (0.5–2 m/s) non-myelinated C fibres.

These terminate in the dorsal (posterior) columns of the spinal cord (Figure 32.1).

• Second-order neurons: carry the pain stimuli to the thalamus (Figure 32.2) via the lateral spinothalamic tracts.
image

Figure 32.1 Anatomy of the spinal cord, showing related sensory and motor areas.

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Figure 32.2 Cross-section of the brain and upper spinal cord.

Synapses are formed by both A and C fibres in the dorsal horns (dorsal or posterior columns) of the spinal cord. There is also regulation of the transmission between the nociceptive neurons and those in the spinothalamic tract. Descending fibres from the higher centres can inhibit transmission.

• Third-order neurons go from the thalamus to the cerebral cortex. The thalamus plays a large role in the integration of pain input, whereas the cortical area deals with the meaningful subjective interpretation of pain and can in some cases override the sensation of pain.

The various pain stimuli are:

• Mechanical.
• Thermal.
• Chemical: can be triggered chemically at the free nerve ending by changes in the concentration of hydrogen ions (H+), serotonin (5-hydroxytryptamine (5-HT)), histamine, bradykinin and eicosanoids (see Figure 32.3, p. 249).

Bradykinin (Figure 32.3) is released when tissue is damaged and so is found in inflammatory processes, e.g. joint inflammation. It stimulates and sensitizes nerve endings, which leads to the stimulus that registers pain with the body. Anti-inflammatories and aspirin inhibit prostaglandin synthesis and therefore the release of mediators that create pain (see Chapter 30 ‘Inflammation and the immune system’, p. 228).

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Figure 32.3 Pain stimulants.

Analgesics

Sites of Action

• At the site of injury, by decreasing the pain caused by an inflammatory reaction: aspirin, non-steroidal anti-inflammatories.
• In neurons, to alter the way the nerve conducts: local anaesthetics.
• In synapses in the dorsal horn: opioids and antidepressants.
• At the level of the brain by affecting the perception of pain: opioids and antidepressants.

Terminology

• Analgesia: refers to the specific blocking of the pain receptors, leaving the function of other receptors, such as touch and temperature, intact.
• Anaesthesia: the blocking of all sensations.

Opioid Receptors

• Location

• Substantia gelatinosa (in the dorsal or posterior column) and central grey matter of the brainstem.

• Subgroups

• Mu and kappa receptors: these are responsible for analgesia and respiratory depression.
• Delta receptors: bind endogenous opiates such as enkephalins, endorphins and dynorphins. These are released as neurotransmitters from specific opiate-containing neurons and modify pain sensation. This quality is exploited by morphine-like drugs.

Pain Pathway Transmitters

• Substance P: see Chapter 31 ‘The nervous system’ (p. 235).
• Other opioid peptides: see Chapter 31 ‘The nervous system’ (p. 235).
• 5-HT (serotonin): see Chapter 31 ‘The nervous system’ (p. 235).
• Excitatory amino acids: see Chapter 31 ‘The nervous system’ (p. 241).

Principles Behind Analgesic Drugs

There are two types of pain:

• Visceral: dull, poorly localized pain, e.g. abdominal pain arising from the peritoneum.
• Somatic: sharply defined, e.g. from a cut on the skin, or a broken bone.

Pain is useful, to a point, because it makes us aware of a diseased organ or damage to the body. Congenital analgesia (congenital insensitivity to pain) is a rare condition in which sufferers do not feel any pain, which makes it life threatening. This is because it is difficult for them to register that they have damaged themselves or have a visceral disease such as peritonitis.

Specific Analgesics

Paracetamol

Paracetamol (Figure 32.4) acts largely as a painkiller and has very little effect on inflammation.

image

Figure 32.4 Chemical structures of painkillers.

• Side Effects

• Allergic skin reactions.
• Paracetamol in large doses can be lethal (see Chapter 7 ‘Free radicals’, p. 49).

Opioid Analgesics

The opiate-based drugs alter the perception and response to pain.

• Morphine

Morphine has a depressant effect on the body by acting centrally on the mu opiate receptors in the CNS and peripheral tissues. CNS effects (general opioid action including derivatives to a lesser degree) are:

• Analgesia: including euphoria and sedation. Particularly useful if a patient is terminal or in a great amount of pain.
• Depression of the vasomotor centre: leading to hypotension.
• Depression of respiration and cough suppression: very dangerous, particularly in the critically ill and the elderly.
• Release of antidiuretic hormone: decreases the urination of the patient leading to urinary retention.
• Miosis (constriction of the pupil of the eye).
• Peripheral effects: smooth muscle contraction as opposed to striated, which is the voluntary muscles.
• Reduced motility of the gastrointestinal tract with accompanying reduced secretion: for this reason, many morphine-derived preparations cause constipation.
• Biliary spasm.
• Constriction of the bronchi partly as a result of histamine release: this adds to the problem of the breathing induced by morphine’s action on the CNS.
• Vasodilatation: a flushing on the skin and itching.
• Nausea and vomiting.

A slow-release oral form is usually used because morphine has a high first-pass metabolism. About 90% of the dose leaves the body within 24 hours.

Adverse Effects

These are usually an extension of the pharmacological effects:

• problems breathing
• hypotension
• nausea and vomiting
• constipation
• tremor
• skin reaction and itching
• addiction to the drug and tolerance if used over a long period of time.

Types of Morphine Administration

Oral

Not the most effective way to give lasting relief because morphine is subject to a high first-pass metabolism (see Chapter 17 ‘Metabolism’, p. 129). Manufacturers have, however, produced a slow-release oral preparation.

Intravenous

This is the usual route of administration. In terminal cases, use is made of a pump system that patients can operate independently when pain relief is required. Otherwise morphine can be given intramuscularly or subcutaneously. Very little of the administered drug crosses the well-protected blood–brain barrier. What medication does get there peaks between 30 and 45 minutes after administration.

Drug Interactions

• Morphine delays the absorption of other orally administered drugs.
• Its depressant effects are potentiated by phenothiazines such as chlorpromazine, which are used as antiemetics, and migraine medication and tricyclic antidepressants such as dosulepin.
• Morphine potentiates most hypnotics, e.g. diazepam and some anaesthetics.

Uses

• Pain relievers: visceral and traumatic.
• Cough suppressants: codeine derivatives are used in some cough mixtures, hence it is possible to get addicted to the cough mixtures.
• Antidiarrhoeal agents: not used so much now. Kaolin and morphine used to be used. Kaolin is a clay, which was used to line the gut, acting as a physical barrier to prevent more water loss; the morphine slowed down gut contractions.

• Other Opioid Derivatives

Heroin

• Is more lipid soluble than morphine. As a result, it is absorbed much more easily by phospholipid membranes of cells.
• Is ultimately metabolized in the body to morphine.
• Its abuse is well documented.

Codeine

• Its properties are similar to morphine, but it is a less powerful analgesic.
• Is used as a cough suppressant in cough mixtures.
• Can control diarrhoea.
• Is combined with aspirin or paracetamol as an analgesic.
• Metabolized to morphine in the body.

Pethidine

• Pethidine is a type of opioid.
• Often used as a short-acting pain reliever, particularly in childbirth or biliary and ureteric colic.

Opiate Partial Agonists and Opiate Antagonists

• Buprenorphine

• A partial agonist of mu opiate receptors but acts as an antagonist on kappa receptors (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 140 and Chapter 32 ‘Analgesia and pain relief’, p. 249).
• Has such a high affinity for the receptors that it is difficult to antidote in the case of an overdose.
• It is a potent and long-lasting analgesic.
• Used as a substitute for management of heroin addicts.

Adverse Effects

Similar to opioids.

• Tramadol

• Acts as a partial agonist, which creates only a partial physiological response (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 140) at the mu receptors and by activating 5-HT and noradrenaline (norepinephrine) pathways. Pain is therefore inhibited at a spinal level.
• Low occurrence of respiratory depression and low potential for abuse make this a useful drug for pain relief.
• Can have side effects of nausea and vomiting.

• Carbamazepine (Tegretol)

• Maintains the sodium channels in a closed position, meaning that neurons in the brain become less excitable, thus calming the nervous system and the patient.
• Also used for schizophrenia and bipolar disorders, but at much higher doses.

Adverse Effects

• Drowsiness.
• Fatigue.
• Headache.
• Diplopia (double vision).
• Ataxia.
• Vertigo.
• Dizziness.
• Nausea and vomiting.
• Dry mouth.
• Allergic skin reactions.
• Effects on the formation of blood cells.
• Oedema and fluid retention.

Drug Interactions

• Various antibiotics.
• Drugs working on the nervous system.
• Steroids.
• Cardiac medication.
• Potential for interactions with a wide variety of herbs and supplements.

Migraine Medication

Migraine is a debilitating condition characterized by severe headaches and various other symptoms such as vomiting. It affects about 10% of the population in the UK. The majority of sufferers are women and there appears to be a relationship between the menstrual cycle and migraine attacks. The current theory is that there is a sudden vasodilatation of cranial blood vessels, but the overall cause is not well understood.

• Treatment

NSAIDs and opiate-based painkillers can be used in some cases; otherwise specialized migraine medication has to be used.

Triptans

• The best known is sumatriptan (Imigran; see Figure 32.4), used in the acute stage of the attacks. They are not useful as prophylactics.
• Selective 5-HT (serotonin) agonists: 5-HT is thought to act as a mediator for migraine headache. The triptans either cause constriction of the intracranial blood vessels, leading to a reduction of pressure, or they block the release of proinflammatory neuropeptides from presynaptic nerve terminals.
• Triptans such as sumitriptan can be sprayed up the nose; this is useful in patients who are prone to vomiting.
• Antiemetics can also be used if vomiting is severe.

Adverse Effects

• Drowsiness.
• Transient increase in blood pressure.
• Hypotension.
• Bradycardia or tachycardia.
• Visual disturbances.

Local Anaesthetics

Lidocaine and novocaine are sodium-channel blockers (see Figure 19.6, p. 141 and Figure 31.2, p. 237). When sodium is not allowed to move through the channels, depolarization in the neurons is no longer possible. This means that the neuron will be unable to transmit an action potential; it is this that creates the anaesthesia.

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