Pain and analgesics

Michael C. Lee, Mark Abrahams

Definition of pain

Physiology of nociception

Classification of pain

Clinical evaluation of pain.

• Pharmacotherapy.

Classification of analgesics

Principals of analgesic pharmacotherapy.

• Non-opioid analgesics.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Paracetamol (acetaminophen)

• Opioid analgesics.

Mechanism of action

Classification of opioid analgesics

Pharmacodynamics of opioids

Adverse effects and their management.

• Opioid agonist drugs.

Mixed agonist/antagonist drugs

Partial agonist drugs

Antagonist drugs

Tolerance, dependence and addiction.

• Co-analgesic agents.

Multipurpose adjuvant analgesics

Drugs used in neuropathic pain

Adjuvants used for bone pain.

• Drug treatment of migraine.

Pharmacotherapy of acute migraine

Drugs used in migraine prophylaxis.

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.

Acute pain

such as that experienced after trauma or surgery, typically resolves with healing of the injured tissue, and can usually be effectively managed with the appropriate use of pharmacotherapy. Poorly controlled post-surgical pain is associated with the development of complications such as pneumonia, myocardial ischaemia, paralytic ileus and thromboembolism, as well as an increased risk of the patient developing chronic pain. Effective analgesia in this setting not only reduces patient anxiety and provides subjective comfort, but also helps to blunt autonomic and somatic reflex responses. Effective analgesia can promote early mobilisation and increased appetite, and this, in turn, can improve postoperative outcome. Moreover, research suggests that analgesia given before surgical incision may reduce subsequent postoperative pain. Clinicians have attempted to exploit the concept of pre-emptive analgesia with varying success.

Chronic pain

is commonly defined as pain that persists beyond the period expected for healing, or pain that is associated with progressive, non-malignant disease. Chronic pain may be due to the persistent stimulation of nociceptors in areas of ongoing tissue damage (e.g. chronic pain due to rheumatoid arthritis). In many instances, chronic pain can persist long after the healing of damaged tissue. In some patients, chronic pain presents without any identified ongoing tissue damage or antecedent injury.

Neuropathic pain

is defined as a chronic pain resulting from damage to the nervous system. Neuropathic pain can be due to damage to the peripheral nervous system, such as patients with diabetic or AIDS polyneuropathy, post-herpetic neuralgia, or lumbar radiculopathy, or to the central nervous system, such as patients with spinal cord injury, multiple sclerosis, or stroke. The mechanisms of neuropathic pain remain the subject of much research.

Cancer-related pain

refers to pain that is the result of primary tumour growth, metastatic disease, or the toxic effects of chemotherapy and radiation, such as neuropathies due to neurotoxic antineoplastic drugs.

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.

Clinical use

NSAIDs are among the most commonly prescribed analgesics and, unless contraindicated, are effective and appropriate analgesics for use in acute inflammatory pain. There is much evidence to suggest that NSAIDs are effective in cancer-related pain. The benefit of NSAIDs in chronic non-cancer-related pain is less certain, with efficacy only proven in chronic inflammatory musculoskeletal pain, mainly from studies in rheumatoid arthritis. NSAIDs are generally ineffective in neuropathic pain conditions, and a careful risk–benefit assessment should be made prior to use in view of the side-effects associated with long-term use.

Choice of NSAID and route of administration

There is little difference in the clinical benefit conferred by any particular NSAID. However, NSAIDs differ in their pharmacokinetic properties and side-effects. This should be taken into account when choosing a non-steroidal agent for long-term use. For example, the oxicams (e.g. piroxicam, tenoxicam) are metabolised slowly and have a high degree of enteropathic circulation. These NSAIDs have long elimination half-lives (but also higher incidences of gastrointestinal and renal side-effects).

NSAIDs should be given orally when possible. The same dose of NSAID is equally effective whether injected or taken orally. Topical application of NSAIDs for musculoskeletal pain is an exception as it is effective and is associated with a lower incidence of side-effects.

Side-effects

All NSAIDs are associated with dose-dependent side-effects. In particular, there is a risk of gastrointestinal bleed, renal toxicity and a possibility of cardiac-related complications. The morbidity related to gastrointestinal adverse effects is considerable (~ 5 per 1000 patients per year of treatment) and catastrophic bleeding can occur without any preceding warning symptoms. For this reason, it is recommended that, when used in the longer term, NSAIDs should be prescribed along with an appropriate gastro-protective agent (see p. 531).

COX-2-specific NSAIDs provide analgesia with a reduced risk of GI bleed (but have a similar risk of renal toxicity). Trials have shown a slightly increased risk of cardiac complications in at-risk patients. Subsequent trials, however, have indicated that increased cardiac risk may also be associated with the use of non-selective NSAIDs (possibly as a result of hypertension secondary to fluid retention). Current guidelines suggest that all cyclo-oxygenase-inhibiting drugs should be used with caution in patients with known cardiovascular or cerebrovascular disease, i.e. at the lowest effective dose, and for the shortest possible time.

Paracetamol (acetaminophen)

The major advantage of paracetamol over the NSAIDs is its relative lack of adverse effects; this justifies its use as a first-line analgesic. It can be used on its own, or synergistically with non-steroidal drugs or opioids. Paracetamol is also an antipyretic with very weak anti-inflammatory properties. There is increasing evidence that its analgesic effect is central and results from the activation of descending serotonergic pain-inhibiting pathways, but its primary site of action may still be inhibition of prostaglandin synthesis (via COX-3 inhibition). Its major drawback is the liver toxicity seen in acute overdose due to the accumulation in the liver of benzoquinones.

Nefopam

Nefopam is chemically distinct and pharmacologically unrelated to any presently known analgesic and has been used in Europe for intravenous and oral administration since 1976. It is a racemic mixture of its two enantiomers. Although its mechanism of action remains largely unknown, nefopam is thought to increase the inhibiting tone of serotonergic and noradrenergic/norepinephrinergic descending pathways by inhibiting the synaptic uptake of dopamine, noradrenaline/norepinephrine and serotonin. Compared to NSAIDs and opioids, nefopam has the advantages of minimal effects on platelet aggregation and not depressing the central nervous system.There have been rare fatal overdoses with the oral form of the drug, characterised by convulsions and arrhythmia. Its sympathomimetic action precludes its use in patients with limited coronary reserve, prostatitis and glaucoma. Minor side-effects (nausea, dizziness and sweating) are observed in 15–30% of treated patients. Nefopam has been abused primarily for its psychostimulant effects, which are probably linked to its dopamine-reuptake inhibition properties.

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.

Mechanism of action of opioids

Opioids produce their effects by activating specific G protein-coupled receptors in the brain, spinal cord and peripheral nervous system. There are three major classes of opioid receptor: δ-opioid (OP1,DOR), κ-opioid (OP2,KOR) and μ-opioid (OP3,MOR), that correspond respectively to their endogenous ligands, enkephalin, dynorphin and β-endorphin. Although studies suggest the existence of subtypes of all three major opioid receptor classes, the evidence is controversial and the sub-classification is of little practical value except, perhaps, to explain the change in side-effect profile sometimes seen during opioid rotation in long-term opioid use or cancer-related pain.

Agonist activity at opioid receptors acts to open potassium channels and prevent the opening of voltage-gated calcium channels. This reduces neuronal excitability and inhibits the release of pain neurotransmitters.

Classification of opioid drugs

Opioids have been traditionally classified as strong, intermediate and weak, according to their perceived analgesic properties and propensity for addiction. This approach can be misleading, as it implies that weak opioids such as codeine are less effective but safe. Codeine may be less potent than morphine but can cause respiratory depression if given in sufficient quantities. Codeine-like drugs are also frequently abused. Opioids may also be classified according to their structure. As described later, the properties of opioids may be predicted on the basis of activity on opioid and other receptor systems. The functional classification is probably of most clinical use (Table 18.1).

Table 18.1 Classification of opioids

Opioid pharmacodynamics

Opioids act to reduce the intensity and unpleasantness of pain. The common side-effects are due to their action on different opioid receptors. They include sedation, euphoria, dysphoria, respiratory depression, constipation, pruritis, and nausea and vomiting. It is important to note, however, that many of these side-effects tend to diminish with time as tolerance to the opioid develops. Constipation and dry mouth (leading to increased risk of dental caries) are more resistant to the development of tolerance and remain problems with long-term use. Impairment of hypothalamic function also occurs with long-term opioid use and may result in loss of libido, impotence and infertility.

Adverse effects associated with the use of opioids in acute pain (and occasionally in chronic non-malignant pain) can often be managed simply by reducing the opioid dose or switching to a different opioid. In palliative medicine, unwanted effects related to long-term opioid use are often treated proactively, laxatives for constipation, excessive sedation by methylphenidate or dextroamphetamine. Rotating to another opioid, or using more frequent but smaller doses of opioids may also help.

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

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Tags: Clinical Pharmacology 11e

Jun 18, 2016 | Posted by admin in PHARMACY | Comments Off

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