Pain and analgesics

Published on 02/03/2015 by admin

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Michael C. Lee, Mark Abrahams

Synopsis

Pain and analgesics

‘The work which you are accomplishing is immensely important for the good of humanity, as you seek the ever more effective control of physical pain and of the oppression of mind and spirit that physical pain so often brings with it.’

Pope John Paul II (26 July 1987)¹

Definition of pain

The International Association for the Study of Pain defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. This implies that the degree of pain experienced by the patient may be unrelated to the extent of underlying tissue damage, and that emotional or spiritual distress can add to the patient’s experience of pain (Fig. 18.1).

Fig. 18.1 A model of pain perception. Carr D B, Loese J L, Morris D B (eds) 2005 Narrative, Pain, and Suffering. The Challenge of Narrative to Pain. Progress in Pain Research and Management, vol. 34. IASP Press, Seattle.

This chapter focuses on the use of drugs for pain relief and illustrates the use of many analgesics that may be encountered in clinical practice. However, clinicians should recognise that the experience of pain is influenced by physical, emotional and psychological factors. While drug therapy is an expedient (and familiar) form of treatment, successful management of pain requires a more holistic approach that addresses all the components of pain.²

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).

Fig. 18.2 Schematic representation of nociceptive pathways. Noxious stimuli such as protons (H +), temperature (temp) etc. applied to end-organs activate nociceptors. Injury leads to the release of prostaglandins such as prostaglandin E2 (PGE2), serotonin (5-HT), nerve growth factor (NGF) etc. from damaged cells, bradykinin (BK) from blood vessels and substance P (sP) from nociceptors. These agents either activate nociceptors directly or sensitise them to subsequent stimuli by parallel activation of intracellular kinases by G-protein-coupled receptors and tyrosine kinase receptors. Primary nociceptive afferents (C-fibres, Ad-fibres) of dorsal root ganglion (DRG) neurones synapse on second order neurones (S) in the spinal dorsal horn (magnified in inset). Here, glutamate (Glu) and sP released from primary afferent terminals (A) activate glutamate receptors (NMDA R, AMPA R, mGluRs) and neurokinin-1 (NK-1) receptors, respectively, located postsynaptically on spinal neurones. These synapses are negatively modulated by spinal inhibitory interneurones (I), which employ enkephalins (Enk) or γ-aminobutyric acid (GABA) as neurotransmitters. Spinal neurones convey nociceptive information to the brain and brainstem. Activation of descending noradrenergic/norepinergic and/or serotonergic systems, which originate in the brain and brainstem, leads to the activation of spinal inhibitory interneurones (I) thereby resulting in antinociception (http://encref.springer.de/mp/0002.htm).

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; Na_v1.7 and Na_v1.8.

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:

• Allodynia – pain due to a stimulus which does not normally provoke pain.

• Hyperalgesia – an increased response to a stimulus which is normally painful.

• Paraesthesia – abnormal sensation, e.g. ‘pins and needles’.

• Dyaesthesia – a painful paraesthesia, e.g. burning foot pain in diabetic neuropathy.

Pharmacotherapy

An analgesic is defined as a drug that relieves pain. Analgesics are classified as opioids and non-opioids (e.g. NSAIDs). Co-analgesics or adjuvants are drugs that have a primary indication other than pain but are analgesic in some conditions. For example, antidepressants and anticonvulsants also act to reduce nociceptive transmission in neuropathic pain.

The efficacy and effectiveness of any given analgesic varies widely between individuals. Analgesics also have a relatively narrow therapeutic window, and drug dosages are often limited by the onset of adverse side-effects. For these reasons, an analgesic should be titrated for an individual patient until an acceptable balance is achieved between subjective pain relief and adverse drug effects.

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.