Pain is defined by the International Association for the Study of Pain as ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.’¹ Acute pain is defined as ‘Pain of recent onset and probable limited duration. It usually has an identifiable temporal and causal relationship to injury or disease.’² However, once a patient presents for medical care, severe acute pain has ceased to serve a useful purpose. Whereas in some conditions the nature and progression of the pain may be helpful in making the diagnosis of the underlying pathology, too great a reliance has been placed upon this feature, thereby allowing the patient to suffer needlessly for prolonged periods.^2,³

When severe pain is inadequately relieved it produces pathophysiological and abnormal psychological reactions that often lead to complications. This is important because acute pain is the most common presenting complaint to an emergency department (ED)⁴ and its management forms part of the daily practice of emergency medicine. It should be considered poor patient care not to treat pain while attempting to arrive at a diagnosis. There can be no greater gift to one’s neighbour than to practise, teach and discover more effective methods to relieve pain and suffering.^2,³ Unfortunately, the management of acute pain is often not a specific component of medical training.

Physiology

Pain is one of the most complex aspects of an already intricate nervous system.² A number of theories have been developed to explain the physiology of pain, but none is proven or complete.

In 1965, the Melzack–Wall ‘Gate Control Theory’ emphasized mechanisms in the central nervous system that control the perception of a noxious stimulus, and thus integrated afferent, upstream processes with downstream modulation from the brain.⁵ However, this theory did not incorporate long-term changes in the central nervous system to the noxious input and to other external factors that impinge upon the individual.⁵ Most pain originates when specific nerve endings (nociceptors) are stimulated, producing nerve impulses that are transmitted to the brain. Nociception is the detection of tissue damage by specialized transducers.⁵

It is now recognized that nociceptor function is altered by the ‘inflammatory soup’ that characterizes a region of tissue injury.⁵ The final pain experience is subject to a complex series of facilitatory and inhibitory events that precede pain awareness, such as past experience, anxiety or expectation.⁶ There are two types of nociceptors:⁷

1 Mechanoreceptors, which are present mainly in the skin (also muscle, joints, viscera, meninges) and respond rapidly to pinprick or heat via Aδ, myelinated afferent neurons.

2 Polymodal, which are widely distributed throughout most tissues and are the nerve endings of unmyelinated C-type afferent neurons. These respond to tissue damage caused by mechanical, thermal or chemical insults, and are responsible for the slow onset, prolonged, poorly localized, aching pain following an injury.

Once transduced into electrical stimuli, conduction of neuronal action potentials is dependent on voltage-gated sodium channels.² A number of chemicals are involved in the transmission of pain to the ascending pathways in the spinothalamic tract. These include substance P and calcitonin gene-related peptide, but many others have been identified.^2,^8,⁹ Opioid receptors are present in the dorsal horn, and it is thought that encephalins (endogenous opioid peptides) are neurotransmitters in the inhibitory interneurons.⁷

Phospholipids released from damaged cell membranes trigger a cascade of reactions, culminating in the production of prostaglandins that sensitize nociceptors to other inflammatory mediators, such as histamine, serotonin and bradykinin.⁷

The threshold for the perception of a painful stimulus is similar in everyone, and may be lowered by certain chemicals such as the mediators of inflammation. The discrete cognitive processes and pathways involved in the interpretation of painful stimuli remain a mystery. The cognitive and emotional reactions to a given painful stimulus are variable among individuals, and may be affected by culture, personality, past experiences and underlying emotional state.^2,^5,¹⁰ In addition, intense and ongoing stimuli further increase the excitability of dorsal horn neurons, leading to central sensitization.² With increased excitability of central nociceptive neurons, the threshold for activation is reduced, and pain can occur in response to low intensity, previously non-painful stimuli known as allodynia.² Pain is a complex, multidimensional, subjective phenomenon.¹⁰

Assessment of pain and pain scales

There is no truly objective measurement of pain. Doctors use a variety of methods for determining how much pain a patient feels. These include the nature of the illness or injury, the patient’s appearance and behaviour, and physiological concomitants. None of these is reliable.

Pain scales have been developed because there are no accurate physiological or clinical signs to objectively measure pain. Three scales have become popular tools to quantify pain intensity:^11,¹² the visual analogue scale (VAS), the numeric rating scale and the verbal rating scale.

Visual analogue scale

The VAS usually consists of a 100-mm line with one end indicating ‘no pain’ and the other end indicating the ‘worst pain imaginable’. The patient simply indicates a point on the line that best indicates the amount of pain experienced. The minimum clinically significant change in patient pain severity measured with a 100-mm visual analogue scale is 13 mm.¹³ Studies of pain experience that report less than a 13 mm change in pain severity, although statistically significant, may have no clinical importance.¹³

Numeric rating scale

The patient is asked in the numeric rating scale to choose a number from a range (usually 0–10) that best describes the amount of pain experienced, with zero being ‘no pain’ and 10 being the ‘worst pain imaginable’. This has been used for cardiac ischaemia pain and is also useful in illiterate patients.

Verbal rating scale

The verbal rating scale simply asks a patient to choose a phrase that best describes the pain, usually ‘mild’, ‘moderate’ or ‘severe’.

The use of pain scales has been restricted predominantly to research, where experimental pain is not associated with the strong emotional component of acute pain. In the clinical setting, anxiety, sleep disruption and illness burden are present.⁹ It is difficult to use a unidimensional pain scale to measure a multidimensional process. Using pain intensity alone will often fail to capture the many other qualities of pain and the overall pain experience. The best illustration of this problem is that the same pain stimulus can be applied to two different people with dramatically different pain scores and analgesic requirements.¹⁴ At best the use of pain scales is an indirect reflection of ‘real’ pain, with patient self-reporting still being the most reliable indicator of the existence and intensity of pain.¹⁵

Nevertheless, pain scales are simple and easy to use and are now routine in EDs, with some recommending that they should be a standard part of the triage process.⁴

General principles

Patients in pain should receive timely, effective and appropriate analgesia, titrated according to response.² Thus, there is essentially no role for the intramuscular route for parenteral analgesia, which simply delays the onset of analgesia. The following points should be stressed:

• The correct analgesic dose is ‘enough’, that is, whatever amount is needed to achieve appropriate pain relief.

• A patient’s analgesic requirements should be reviewed frequently. Do not wait for pain to return to its previous level before re-dosing with analgesia. Larger early doses and more frequent doses of analgesia are associated with lower total doses and shorter duration of analgesic use. Some patients have been misled into believing that pain medicine is dangerous, so it is important to explain the safety and efficacy of this approach.

• EDs should have specific policies relating to pain and analgesia.

• Senior clinicians should lead by example.

Specific agents

Opioids

The term ‘opioid’ refers to all naturally occurring and synthetic drugs producing morphine-like effects. Morphine is the standard opioid agonist against which others are judged.¹⁶ These drugs are the most powerful agents available in the treatment of acute pain. A number of specific opioid receptors have been identified. They are responsible for a variety of effects, including analgesia, euphoria, respiratory depression and miosis (μ receptor); cough suppression, sedation (κ); dysphoria, hallucinations (σ); nausea and vomiting, and pruritus (δ).⁷ Opioids act on injured tissue to reduce inflammation in the dorsal horn to impede transmission of nociception, and supraspinally to activate inhibitory pathways that descend to the spinal segment.⁹

Unfortunately, many doctors use opioids inappropriately and there are particular concerns regarding the risks of respiratory depression and inducing iatrogenic addiction. Less than 1% of patients who receive opioids for pain develop respiratory depression.¹⁷ Tolerance to this side effect develops simultaneously with tolerance to the analgesic effect. If the opioid dose is increased so that at least half the pain is relieved, the chance of respiratory depression is small. Further, naloxone will reverse the effects of opioids. In relation to fears of addiction, large studies have shown that inducing this following opioid analgesia use is exceedingly rare.¹⁸

From a clinical practice point of view, many patients who require intravenous opioid will also require admission to hospital, as there will be ongoing opioid requirements that can only be administered in hospital. There have been occasions where patients have received opioid analgesia that has relieved their pain, and they have then been discharged without a final diagnosis. This is an unacceptable practice. A patient may present with abdominal pain with vomiting, and, for instance, a provisional diagnosis of gastroenteritis is made. After opioid analgesia is given the patient may feel better and be discharged. A diagnosis such as appendicitis or bowel obstruction has not been excluded.

It is therefore necessary for patients to have an appropriate diagnostic evaluation to confirm a benign cause, and to reassess the patient after the opioid effects have waned. For patients in whom the final diagnosis is certain, such as in anterior shoulder dislocation, discharge is appropriate after a suitable period of observation until the patient is deemed clinically fit for discharge. This is a different scenario from that described previously, as it is a single system problem in which there is no doubt about the diagnosis. In summary, pain that is considered severe enough to warrant intravenous opioid analgesia usually requires a high index of suspicion for significant pathology.

Route of administration

Opioids may be administered by many routes, including oral, subcutaneous, intramuscular, intravenous, epidural, nebulized, intrapleural, intranasal, intra-articular and transdermal. All may have a role in a specific clinical situation.⁴ There is a good rationale for the use of the intravenous route in moderate-to-severe pain⁴ and titration of intravenous opioids remains the standard of care for acute severe pain.

Morphine

The standard intravenous morphine dose is 0.1–0.2 mg/kg or more with a duration of action of 2–3 h. This should be initiated as a loading dose of opioid to provide rapid initial pain relief aiming for an optimal balance between effective pain relief and minimal side effects. This means tailoring the approach to each individual patient. Thus, a young fit healthy man with renal colic may require an initial bolus of 0.1 mg/kg morphine, followed by further increments of 2.5–5 mg. Conversely, a frail elderly patient may only tolerate 1.0–2.5 mg morphine total to begin with. There may also be considerable inter-individual variation in response to analgesia. Procedural pain may require higher-dose opioid analgesia, which has been found to be well-tolerated and safe.¹⁹ Appropriate monitoring and resuscitation equipment should be available to maximize safety.

Rapid pain relief and titration to effect are obvious advantages. Intramuscular administration results in unreliable and variable absorption, and older routine practices such as prescribing ‘75 mg pethidine i.m.’ are deplorable and take no account of an individual’s requirements.⁷ Oral opioids tend to be underused in the ED, but are effective for all levels of pain.

Special considerations

Pethidine

Pethidine should be used with caution in patients with renal failure, as there is increased risk of central nervous system toxicity due to the toxic metabolite, norpethidine. Norpethidine causes tremor, twitching, agitation and convulsions.¹⁶ Also pethidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors, as they interfere with pethidine metabolism, increasing the likelihood of toxicity.²⁰ Finally, pethidine may trigger the serotonin syndrome if used concomitantly with selective serotonin re-uptake inhibitors (SSRIs). Pethidine has approximately one-eighth the potency of morphine and causes the same degree of bronchospasm and increased biliary pressure as morphine.² Its use is declining and should continue to be discouraged in favour of other opioids.²

Fentanyl

Allergic reactions are extremely rare with opioids. Fentanyl does not release histamine, making it ideal for treating patients with reactive airways disease. There are advantages in using fentanyl for brief procedures in the ED because of its short half-life. The intravenous dose of fentanyl is 1–2 μg/kg or more with a duration of action of 30–60 min. High doses of fentanyl may produce muscular rigidity, which may be so severe as to make ventilation difficult, but which responds to naloxone or muscle relaxants. Intranasal fentanyl is an effective analgesic in the ED and in the pre-hospital setting.²

Codeine

Codeine is the most commonly used oral opioid prodrug. Unfortunately, up to 6–10% of the Caucasian population, 2% of Asians, and 1% of Arabs have poorly functional cytochrome P450 2D6 (CYP2D6), which may render codeine largely ineffective for analgesia in these patients, although some analgesic efficacy may occur via alternate cytochrome P450 pathways.

Prescribed alone in doses as high as 120 mg, codeine has been demonstrated to be no more effective than placebo in both the adult and geriatric populations, while causing increasing gastrointestinal side effects such as nausea, vomiting and constipation with increasing doses.⁴ It is frequently given in combination with paracetamol or aspirin.

Tramadol

Tramadol is a new opioid, with novel non-opioid properties.²¹ Its efficacy lies between codeine and morphine. It has a relative lack of serious side effects such as respiratory depression, and the potential for abuse and psychological dependence is low.²¹ Other side effects such as nausea, vomiting, dizziness and somnolence may be troublesome, and there is a risk of seizures.^21,²² Thus, it should be avoided or used with caution in patients who are taking other drugs that reduce the seizure threshold such as tricyclic antidepressants and SSRIs. Also the concomitant administration of tramadol with monoamine oxidase inhibitors, or within 2 weeks of their withdrawal, is contraindicated.²¹

The role of tramadol in emergency medicine is yet to be defined. One review concluded that tramadol does not offer any particular benefits over existing analgesics for the majority of emergency pain relief situations,²² with oral doses having equivalent analgesic effects in mild-to-moderate severity acute pain compared with currently available analgesics.²² Intravenous tramadol is less effective than intravenous morphine.²²

However, tramadol may be useful in certain situations:²²

• for patients in whom codeine is not effective

• where NSAIDs are contraindicated

• for the treatment of chronic pain.

Non-steroidal anti-inflammatory drugs (NSAIDs) are either non-selective cyclo-oxygenase (COX) inhibitors or selective inhibitors of COX-2 (COX-2 inhibitors). NSAIDs are effective analgesic agents for moderate pain, specifically when there is associated inflammation.⁴ As with opioids, there are multiple routes of administration available. Unfortunately, their use in acute severe pain is limited by the length of onset time of 20–30 min. There is no clear superiority of one agent over another.

There is up to a 30% incidence of upper gastrointestinal bleeding when NSAIDs are used for over 1–2 weeks. The risk of bleeding in the elderly for short (3–5 days) acute therapy appears to be minimal.⁴ NSAID use in pregnancy (especially late) is not recommended. Ibuprofen is considered the NSAID of choice in lactation.

NSAIDs have a spectrum of analgesic, anti-inflammatory and antipyretic effects and are effective analgesics in a variety of pain states.² Unfortunately, significant contraindications and adverse effects limit the use of NSAIDs, many of these being regulated by COX-1.² NSAIDs are useful analgesic adjuncts and hence NSAIDs are therefore integral components of multimodal analgesia.² NSAID side effects are more common with long-term use. The main concerns are renal impairment, interference with platelet function, peptic ulceration and bronchospasm in individuals who have aspirin-exacerbated respiratory disease.² In general, the risk and severity of NSAID-associated side effects is increased in elderly people.²

Caution is therefore needed in the elderly and in patients with renal disease, hypertension and heart failure, or with asthma. NSAIDs reduce renal cortical blood flow and may induce renal impairment, especially when used in patients already on diuretics. In patients with asthma, 2–20% are aspirin sensitive and there is a 50–100% cross-sensitivity with NSAIDs.

Ketorolac is a parenteral NSAID that is equipotent to opioids, with ketorolac and morphine equivalent in reducing pain. There is a benefit favouring ketorolac in terms of side effects, when ketorolac is titrated intravenously for isolated limb injuries.^23,²⁴ However, the utility of ketorolac in acute pain is limited due to a prolonged onset of action and a significant number of patients (25%) who exhibit little or no response.²⁵ There is also benefit using ketorolac for acute renal colic.^23,²⁶ A combination of morphine and ketorolac offered pain relief superior to either drug alone and was associated with a decreased requirement for rescue analgesia in patients with renal colic.²⁷ Rectal NSAIDs are an effective alternative to parenteral NSAIDs in the treatment of renal colic.

Paracetamol

Paracetamol is an effective analgesic for acute pain ² and has useful antipyretic activity.²⁸ The addition of an NSAID further improves efficacy.² Paracetamol inhibits prostaglandin synthetase in the hypothalamus, prevents release of spinal prostaglandin, and inhibits inducible nitric oxide synthesis in macrophages.²⁸

Indications for paracetamol include mild pain, particularly of soft tissue and musculoskeletal origin, mild procedural pain, supplementation of opioids in the management of more severe pain allowing a reduction in opioid dosage, and as an alternative to aspirin.²⁸ Paracetamol has no gastrointestinal side effects of note and may be prescribed safely in patients with peptic ulcer disease or gastritis.⁴ Aspirin has the risk of gastrointestinal side effects, such as ulceration and bleeding. It also has an antiplatelet effect, which lasts for the life of the platelet.

Paracetamol is rapidly absorbed with a peak concentration reached in 30–90 min.²⁸ The recommended adult dose is 0.5–1 g every 4–6 h to a generally accepted maximum of 4 g per day.²⁸ Paracetamol has a low adverse event profile and is an excellent analgesic, especially when used in adequate dose. Chronic use of paracetamol alone does not seem to cause analgesic nephropathy.²⁸ It can be used safely in alcoholics and patients with liver metastases.^28,²⁹

Combination drugs

Non-opioid agents, e.g. paracetamol, NSAIDs and paracetamol/codeine combinations, are all useful analgesics for mild-to-moderate pain. A systematic review found that paracetamol–codeine combinations in single dose studies produce a slightly increased analgesic effect (5%) compared with paracetamol alone.³⁰ However, none of the studies reviewed were based in the ED. In multidosage, paracetamol–codeine preparations have significantly increased side effects.³⁰ However, other reports state that the combination of paracetamol 1000 mg plus codeine 60 mg has a number needed to treat of 2.2.² NSAIDs have a higher rate of serious adverse effects.

Other analgesic agents

Nitrous oxide

Nitrous oxide is an inhalational analgesic and sedative which, in a 50% mixture with oxygen (Entonox®), has equivalent potency to 10 mg morphine in an adult.⁷ The Entonox® delivery system uses a preferential inhalational demand arrangement for self-administration, which requires an airtight fit between the mask/mouthpiece and face. As the patient holds the mask/mouthpiece their grip will relax if drowsiness occurs, the airtight seal will be lost and the gas flow stops, thereby avoiding overdosage.

This system requires a degree of patient involvement and cooperation, and is useful for patients who have difficult intravenous access or are needle-phobic. Patients who are elderly, young, confused or uncooperative will not find the technique effective. Nitrous oxide increases the volume of a pneumothorax or any other gas-filled cavity, so is contraindicated in patients with pneumothorax or pneumoperitoneum.

Sumatriptan

Sumatriptan is a 5HT₁ receptor agonist that is effective for the treatment of acute migraine in a high proportion of patients. The dose is 50 mg orally, or 6 mg subcutaneously if the patient is vomiting. Ideally, it should be taken at the onset of headache, but is still effective when the headache is established. In about one-third to one-half of patients the headache returns within 24 h, but is almost always responsive to a second tablet.³¹

Sumatriptan is not an analgesic and should not be used for non-vascular headache, or for migraine aura with early evolving headache, or as a diagnostic test for migraine. Contraindications include pregnancy, ischaemic heart disease or chest pain with previous use, uncontrolled hypertension, ergotamine in the previous 24 h, and current or recent (within 2 weeks) therapy with MAO inhibitors.

Acute migraine headache requires a stepwise approach to the use of pharmacological agents. Moderate-to-severe migraine may warrant the use of specific antimigraine medications such as ergotamine or sumatriptan, unless contraindicated.² The combination of aspirin (900 mg) and metoclopramide is as effective as sumatriptan in the treatment of migraine, is better tolerated and also cheaper.² Intravenous prochlorperazine is more effective than metoclopramide or rectal prochlorperazine, although is unlicensed for this delivery mode.² The use of opioids is not recommended.²

Ketamine

Ketamine is an N-methyl-D-aspartate (NMDA) antagonist. It is a unique anaesthetic that induces a state of dissociation between the cortical and limbic systems to produce a state of dissociative anaesthesia, with analgesia, amnesia, mild sedation and immobilization. It does not impair protective airway reflexes, and random or purposeful movements are frequently observed in patients after administration. Side effects include hypersalivation, vomiting, emergence reactions, nightmares, laryngospasm, hypertension, tachycardia and increased intracranial pressure.^32,³³

Unfortunately, there are many potential contraindications to ketamine use including upper or lower respiratory infection, procedures involving the posterior pharynx, cystic fibrosis, age younger than 3 months, head injury, increased intracranial pressure, acute glaucoma or globe penetration, uncontrolled hypertension, congestive cardiac failure, arterial aneurysm, acute intermittent porphyria and thyrotoxicosis.³³ Despite this, ketamine is used increasingly in the EDs as part of procedural sedation (see Ch. 22.3). It is also an effective analgesic especially for opioid resistant pain.

Pain relief in pregnancy

Non-pharmacological treatment options should be considered where possible for pain management in pregnancy, because most drugs cross the placenta.² Use of medications for pain in pregnancy should be guided by published recommendations.² Paracetamol is regarded as the analgesic of choice.² NSAIDs are used with caution in the last trimester of pregnancy and should be avoided after the 32nd week.² The use of NSAIDs is associated with increased risk of miscarriage.² Overall, the use of opioids to treat pain in pregnancy appears safe.²

Non-pharmacological therapies

Although pain perception involves neuro-anatomical processes, the other interrelated component of pain reaction is psychophysiological. The use of non-pharmacological techniques is therefore vitally important. These include empathy, a compassionate approach, a calm manner and reassurance. Immobilization of fractures with splinting is effective, as is the application of ice to a wound. Other techniques, such as hypnosis, transcutaneous nerve stimulation and manipulation have not been widely studied in the ED setting.

Special pain situations and non-analgesic agents

Whilst this chapter has focused on specific analgesic agents, there are many miscellaneous agents that are effective in providing disease-specific analgesia. Examples of these include:

• sumatriptan (see earlier)

• glyceryl trinitrate and beta blockers for acute cardiac ischaemia pain

• redback spider antivenom for latrodectism

• antiviral agents for herpes zoster

• antidepressants or anticonvulsants for neuropathic pain

• oxygen therapy for cluster headache

• calcium gluconate for hydrofluoric acid burns

• hot water (43 °C) for venomous marine stings.

In addition, adjuvant therapy with anxiolytics such as midazolam contributes to pain relief. Obtaining a definitive diagnosis allows directed therapy that contributes to pain relief. If specific treatments appear to be ineffective, then the diagnosis should be reconsidered.

Chronic pain

Chronic pain ‘commonly persists beyond the time of healing of an injury and frequently there may not be any clearly identifiable cause.’² Patients with chronic pain attend the ED with exacerbations of their chronic pain. They are often taking multimodal therapies prescribed by a pain specialist. The main difference between acute and chronic pain is that in chronic pain central sensitization is the main underlying pathophysiology.³⁴ It is important to avoid a judgemental attitude to these patients as there is a risk of overlooking serious pathology.

Co-analgesics in the setting of chronic pain, especially ketamine, are of particular value in those with poor opioid responsiveness.² These patients appear to benefit from several days of a ketamine infusion. Other agents may be useful for neuropathic pain.

The other issue with chronic pain is to be aware of adjuvant therapies for decreasing the likelihood of chronic pain developing. For example, early management of acute zoster infection may reduce the incidence of post-herpetic neuralgia.² Aciclovir given within 72 h of onset of the rash accelerates the resolution of pain and reduces the risk of post-herpetic neuralgia.² Amitriptyline 25 mg daily in patients over 60 years for 90 days, started at the onset of acute zoster, reduces pain prevalence at 6 months post-zoster infection.³⁵