Pain is a subjective phenomenon and quantitative assessment is difficult (Breivik et al., 2008). The most commonly used instruments are visual analogue and verbal rating scales. Visual analogue scales are 10 cm long lines labelled with an extreme at each end; usually ‘no pain at all’ and ‘worst pain imaginable’. The patient is required to mark the severity of the pain between the two extremes of the scale. Verbal rating scales use descriptors such as ‘none’, ‘mild’, ‘moderate’ and ‘excruciating’. More elaborate questionnaires such as the Brief Pain Inventory and the McGill Pain Questionnaire help to describe other aspects of the pain, and pain diaries record the influence of activity and medication on pain.

Management

Acute pain usually results from noxious stimulation as a result of tissue damage or injury. It can be managed effectively using analgesic drugs and is often self-limiting.

Persistent pain may be considered as pain which continues beyond the usual time required for tissue healing. Treatment may involve specialist pain management services, hospices and a multidisciplinary approach that assesses and manages patients using a biopsychosocial approach. Initial treatment is usually directed at the underlying disease process where possible, for example, medication, surgery or anti-tumour therapy. However, non-medical treatments such as physical therapy and various psychological techniques including cognitive behavioural therapy may also form part of a multi-modal treatment programme. Pain can be modulated using non-pharmacological techniques: for example, stimulation-produced analgesia such as transcutaneous electrical nerve stimulation (TENS), acupuncture and massage, or invasive procedures such as neurosurgery or neurolytic nerve blocks.

Analgesic ladder

The World Health Organization (WHO) analgesic ladder (Fig. 33.2) forms the basis of many approaches to the use of analgesic drugs. There are essentially three steps: non-opioid analgesics, weak opioids and strong opioids. The analgesic efficacy of non-opioids, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen and diclofenac), is limited by side effects and ceiling effects, that is, beyond a certain dose, no further pharmacological effect is seen. If pain remains uncontrolled, then a weak opioid, such as codeine or dihydrocodeine, may be helpful. There may be additional benefit in combining a weak opioid with a non-opioid drug, although many commercial preparations contain inadequate quantities of both components and are no more effective than a non-opioid alone. Strong opioids, of which morphine is considered the gold standard, have no ceiling effect and therefore increased dosage continues to give increased analgesia but side effects often limit effectiveness. Adjuvant drugs, such as corticosteroids, antidepressants or anti-epileptics, may be considered at any step of the ladder.

Fig. 33.2 WHO three-step analgesic ladder.

Analgesic drugs

Paracetamol

Despite being used in clinical practice for over 50 years and much investigation, the mechanism by which paracetamol exerts its analgesic effect remains uncertain. Inhibition of prostaglandin synthesis within the CNS has been proposed, although this is probably not the only mechanism. Interaction with the serotonin (Tjolsen et al., 1991) and endocannabinoid (Högestätt et al., 2005) neurotransmitter systems have been demonstrated in animal models.

Following oral administration the bioavailability of paracetamol is around 60%, but if given by the rectal route it is much lower and much more variable. A formulation for intravenous infusion has been promoted over the last few years and this has largely replaced the rectal route of administration. Therapeutic plasma levels are reached within 30 min of oral administration. The elimination half-life of paracetamol is relatively short (t_½ = 2–4 h); hence, frequent dosing is required to maintain its analgesic effect.

With normal doses, the majority of paracetamols are metabolised and inactivated in the liver, undergoing a phase II conjugation reaction with glucuronic acid (Fig. 33.3). A small P450 mediated reaction that forms a reactive intermediate, N-acteyl-p-benzoquinimine (NAPQI). Usually, NAPQI can be deactivated by conjugation with glutathione in the liver. However, following ingestion of a large amount of paracetamol the hepatic stores of both glucuronic acid and glutathione become depleted leaving free NAPQI, which causes liver damage.

Fig. 33.3 Paracetamol metabolism in humans.

The usual therapeutic dose for adults is paracetamol 1 g taken four times daily. It is very important that this dose is not exceeded, otherwise hepatotoxicity is more common. This may be particularly problematic for malnourished adults with low body weight (Claridge et al., 2010). A reduced maximum daily infusion dose (3 g/24 hours) is recommended for patients with hepatocellular insufficiency, chronic alcoholism or dehydration. Paracetamol is also available as an over-the-counter (OTC) medicine and is a component of many cold and influenza remedies. Compared with other analgesics, paracetamol is not as potent; however, when taken in combination with a NSAID or opioid, there is an additive analgesic effect.

Non-steroidal anti-inflammatory drugs

Mode of action

NSAIDs exert their analgesic and anti-inflammatory effects through inhibition of the enzyme cyclo-oxygenase. NSAIDs are used widely to relieve pain, with or without inflammation, in people with acute and persistent musculoskeletal disorders. In single doses, NSAIDs have superior analgesic activity compared to paracetamol (Hyllested et al., 2002). In regular higher dosages, they have both analgesic and anti-inflammatory effects, which makes them particularly useful for the treatment of continuous or regular pain associated with inflammation. NSAIDs have been shown to be suitable for the relief of pain in dysmenorrhoea, toothache and some headaches and to treat pain caused by secondary bone tumours, which result from lysis of bone and release of prostaglandins.

Weak opioids

Weak opioids are prescribed frequently, either alone or in combination with other analgesics, for a wide variety of painful disorders. There are three major drugs in this group, codeine, dihydrocodeine and dextropropoxyphene, which are recommended as step 2 of the WHO analgesic ladder for pain that has not responded to non-opioid analgesics. Despite this recommendation, there is little data which demonstrates that weak opioids are of any benefit in the relief of persistent pain, and it may be more beneficial to use a smaller dose of a strong opioid.

Co-proxamol, a combination of dextropropoxyphene and paracetamol, was withdrawn in the UK in 2007 following safety concerns, particularly toxicity in overdose. An unlicensed product remains available for patients who find it difficult to change to alternative treatment.

Codeine

Codeine is the prototypical drug in this group. It is structurally similar to morphine and about 10% of the codeine is demethylated to form morphine, and the analgesic effect may be due to this, at least in part. It is a powerful cough suppressant as well as being very constipating. In combination with NSAIDs, the analgesic effects are usually additive but the variability in response is considerable. A degree of genetic polymorphism occurs within the population such that the hepatic microsomal enzyme CYP2D6 that is responsible for the conversion of codeine to morphine does not catalyse this conversion in approximately 8% of the Caucasian population. The duration of analgesic action is about 3 h.

Dihydrocodeine

Dihydrocodeine is only available in a few countries and is chemically similar to codeine. It has similar properties to codeine when used at the same dosage and may be slightly more potent.

Dextropropoxyphene

Historically, dextropropoxyphene was prescribed in combination with other analgesics such as paracetamol (co-proxamol). There are few data on its therapeutic value, and at least one review concluded that analgesic efficacy is less than aspirin and barely more than placebo. At best, dextropropoxyphene failed to show any superiority over paracetamol (Li Wan Po and Zhang, 1997). At worst, it is a dangerous drug which has the potential for steadily developing toxicity. Patients with hepatic dysfunction and poor renal function are particularly at risk. It is associated with problems in overdose, notably a non-naloxone reversible depression of the cardiac conducting system. Dextropropoxyphene interacts unpredictably with a number of drugs, including carbamazepine and warfarin. In 2005, the Medicines and Healthcare products Regulatory Agency (MHRA) announced concerns about the safety and effectiveness of co-proxamol and directed that it should be withdrawn from clinical use in the UK; however, it still remains available as an unlicensed medicine for the small number of patients who do not obtain analgesia with other analgesic medicines.

Strong opioids

Morphine

Morphine is the ‘gold standard’ strong opioid analgesic. It is available for administration by a range of administration routes, including oral, rectal and injectable formulations and has a duration of action of about 4 h after oral administration. There is no ceiling effect when the dose is increased. A general protocol for morphine use to obtain rapid relief from acute pain is to use intravenous bolus doses of 2–5 mg titrated until pain relief is achieved. In the initial management of persistent non-cancer pain or cancer pain, an oral regimen is more appropriate using an immediate-release formulation. A usual starting dose is 5–10 mg every 4 h, and the patient should be advised to take the same dose as often as is necessary for breakthrough pain. It may be necessary to double the dose every 24 h until pain relief is achieved, although a slower dose escalation will often suffice. After control is achieved, it is usual to change to an oral modified release formulation, which allows less frequent dosing, either daily or twice-daily. There is no ceiling dose for the analgesic effect of morphine; daily doses of up to 1 or 2 g of morphine may be required for some cancer patients, but relatively few require more than about 200 mg daily. Morphine is metabolised in the liver and one metabolite, morphine 6-glucuronide, is pharmacologically active and this should be taken into consideration in patients who have renal failure.

Other strong opioids

Opioids such as pethidine and dextromoramide offer little advantage over morphine in that they are generally weaker in action with a relatively short duration of action (2 h). Dipipanone is only available in a preparation which contains an antiemetic (cyclizine), and increasing doses lead to sedation and the risk of developing a tardive dyskinesia with long-term use. Methadone has a long elimination half-life of 15–25 h, and accumulation occurs in the early stages of use. It has minimal side effects with long-term use and some patients who experience serious adverse effects with morphine may tolerate methadone.

Hydromorphone and oxycodone are synthetic opioids that have been used for many years in North America and more recently in Europe. They are available in both immediate and modified release preparations. Some patients appear to tolerate hydromorphone or oxycodone better than morphine but there is no evidence to suggest which patients achieve the best effect with either of these drugs.

Fentanyl is available as a transdermal formulation for long-term use. The patch is designed to release the drug continuously over 3 days. When starting the drug, alternative analgesic therapy should be continued for at least the first 12 h until therapeutic levels are achieved, and an immediate acting opioid should be available for breakthrough pain. Patches are replaced every 72 h.

The relative potencies of the commonly used opioids are summarised in Table 33.1.

Table 33.1 Relative potencies of opioid drugs

Drug	Potency (morphine = 1)
Codeine	0.1
Dihydrocodeine	0.1
Tramadol	0.2
Pethidine	0.1
Morphine	1
Diamorphine	2.5
Hydromorphone	7
Methadone	2–10 (with repeat dosing)
Fentanyl (transdermal)	150

Clinical considerations

Use of opioids is almost universally accepted in cancer pain but many patients with persistent non-cancer pain can find considerable relief with strong opioids; however, barriers to their use in this context appear to be based more on ignorance and political fashions than clinical evidence (Ballantyne and Mao, 2003). As a general rule, strong opioids effective in the management of neuropathic and musculoskeletal pain, including osteoarthritis, are less effective for sympathetically maintained pain.

Agonist-antagonist and partial agonists

Most of the drugs in this category are either competitive antagonists at the μ opioid receptor, where they can bind to the site but exert no action, or they exert only limited actions; that is, they are partial agonists. Those that are antagonists at the μ opioid receptor can provoke a withdrawal syndrome in patients receiving concomitant opioid agonists such as morphine. These properties make it difficult to use these agents in the control of persistent pain, and the process of conversion from one group of drugs to another can be complex.

Buprenorphine

Buprenorphine is a semi-synthetic, highly lipophilic opioid that is a partial agonist at the μ opioid receptor and an antagonist at both the δ and κ receptors. It undergoes extensive metabolism when administered orally and to avoid this effect, it is given sublingually. It has high receptor affinity and, through this property, a duration of action of 6 h.

A long duration of action and high bioavailability would suggest a role for buprenorphine in the management of persistent pain. Relatively recently, buprenorphine has been marketed as a transdermal formulation and may be an effective alternative to other strong opioids for persistent non-cancer pain. There is limited evidence of efficacy in osteoarthritis and low back pain. Following sublingual or intravenous administration the incidence of nausea and vomiting appears to be substantially higher than with morphine; however, respiratory depression and constipation are less frequent.

Pentazocine

Pentazocine, a benzomorphan derivative, is an agonist and at the same time a very weak antagonist at the μ opioid receptor. This drug became popular in the 1960s, when it was thought it would have little or no abuse potential. This is now known to be untrue, although its abuse potential is less than that of the conventional agonists such as morphine. It produces analgesia that is clearly different from morphine and is probably due to agonist actions at the κ-receptor. There are no detailed studies of its use in persistent pain, but its short duration of action (about 3 h) and the high incidence of psychomimetic side effects make it a totally unsuitable drug for such use.

Tramadol

Tramadol is a centrally acting analgesic that has opioid agonist activity and also has potent monoamine reuptake properties similar to many antidepressants. Indeed, tramadol appears to have intrinsic antidepressant activity. It is not as potent as morphine and efficacy is limited by side effects, including an unfavourably high risk of drowsiness and nausea and vomiting. Its monoaminergic activity appears to be valuable in the management of neuropathic pain and hence may be an acceptable alternative to a weak opioid.

Adverse effects of opioids

The adverse effects of opioids are nearly all dose related, and tolerance develops to the majority with long-term use.

Respiratory depression

Respiratory depression is potentially dangerous in patients with impaired respiratory function, but tolerance develops rapidly with regular dosing. It can be reversed by naloxone.

Sedation

Sedation is usually mild and self-limiting. Smaller doses, given more frequently, may counteract the problem. Rarely, dexamfetamine or methylphenidate has been used to counteract this effect.

Nausea and vomiting

Antiemetics should be co-prescribed routinely with opioids for the first 10 days. Choice of antiemetic will depend upon the cause, and a single drug will be sufficient in two-thirds of patients. Where nausea is persistent, additional causes should be sought and prescribing reviewed. If another antiemetic is used, it should have a different mode of action.

Constipation

Opioids reduce intestinal secretions and peristalsis, causing a dry stool and constipation. Unlike other adverse effects constipation tends not to improve with long-term use, and when opioids are used on a long-term basis most patients need a stool softener (e.g. docusate sodium) and a stimulant laxative (e.g. senna) regularly. Dosage should be titrated to give a comfortable stool. High-fibre diets and bulking agents do not work very well in preventing constipation in patients on opioids. Co-danthrusate (dantron + docusate sodium) and co-danthramer (dantron + poloxamer 188) are alternatives; however, because of the potential carcinogenicity and genotoxicity of dantron, they are only indicated for use in terminal care.

Tolerance, dependence and addition

Persistent treatment with opioids often causes tolerance to the analgesic effect, although the mechanism remains unclear (Holden et al., 2005). When this occurs the dosage should be increased or, alternatively, another opioid can be substituted, since cross-tolerance is not usually complete. Addiction is very rare when opioids are prescribed for pain relief.

Smooth muscle spasm

Opioids cause spasm of the sphincter of Oddi in the biliary tract and may cause biliary colic, as well as urinary sphincter spasm and urinary retention. Thus, in biliary or renal colic, it may be preferable to use another drug without these effects. Pethidine was believed to be the most effective in these circumstances but the evidence for this has been questioned (Thompson, 2001).

There is increasing evidence that long-term use of potent opioids may cause clinically significant adverse effects on the endocrine system, namely testosterone deficiency. Effects on the immune system are also under scrutiny.

Special techniques of opioid drug delivery

Patient-controlled analgesia (PCA)

PCA is a system which allows the patient to titrate the dose of opioid to suit their individual analgesic requirements. The drug is delivered using a syringe attached to an electronic or elastomeric pump, which delivers a preset dose when activated by the patient depressing a button. A lock-out period, during which the machine is programmed not to respond, ensures that a second dose is not delivered before the previous one has had an effect. Some devices allow an additional background infusion of drug to be delivered continuously. A maximum dose facility ensures that the machine does not deliver more than a preset dose over a given time. PCA is a useful technique for the management of pain after surgery. The system is convenient and enjoys a high degree of patient acceptability.

The traditional intermittent intramuscular injection of opioids can be effective but is less versatile than titrated intravenous administration. The subcutaneous route is subject to most of the problems associated with intramuscular administration but tends to be less painful.

Opioid use via any route is associated with nausea, and antiemetics should be prescribed routinely. Administration of compound preparations containing both opioids and antiemetics is not recommended as few preparations contain drugs with similar pharmacokinetic profiles and accumulation, usually of the antiemetic, may occur.

Epidural analgesia

Epidural injections and infusions may be effective in relieving pain arising from both malignant causes and non-cancer diseases and are very effective in postoperative and labour pain. Various combinations of local anaesthetics, opioids or steroids can be administered into the epidural space near to the spinal level of the pain.

Epidural opioids

Effective analgesia can be obtained by administering small doses of opioids to the epidural space. As there are opioid receptors in the spinal cord, smaller doses than administered by other parenteral routes are required and may be given with and without long acting local anaesthetic drugs. However, severe respiratory depression, nausea and vomiting, urinary retention and pruritus can occur after their use. Life threatening respiratory depression can occur when additional opioids are given by other routes to patients already receiving epidural opioids, and this practice should be actively discouraged. Respiratory depression which occurs soon after administration, due to intravascular absorption, is relatively common and simple to detect and treat. However, respiratory depression can also occur many hours after opioid administration. This is most common with morphine, probably because of its lower lipophilicity compared with fentanyl and diamorphine. Fentanyl has much greater stability than diamorphine and it can be prepared with bupivacaine in a terminally sterilised formulation which minimises the risk of adding the incorrect dose to an infusion fluid in a clinical environment and maintains sterility.

Local anaesthetics

Local anaesthetic drugs, such as lidocaine and bupivacaine, produce reversible blockade of neural transmission in automonic, sensory and motor nerve fibres by binding to sodium channels in the axon membrane from within, preventing sodium ion entry during depolarisation. The threshold potential is not reached, and consequently the action potential is not propagated. The concentration of local anaesthetic and dose used determine the onset, density and duration of the block. There are marked differences in the recommended maximum safe doses of different local anaesthetic agents. If the maximum dose is exceeded, serious cardiovascular (arrhythymias) and CNS effects (convulsions) may be observed.

Local anaesthetic drugs injected close to a sensory nerve or plexus will block the conduction of nerve impulses, including pain from sensory fibres and provide excellent analgesia. Some local anaesthetics are given with adrenaline (epinephrine) to reduce systemic toxicity and increase the duration of action.

Local anaesthetics can be applied directly to wounds or by local infiltration to produce postoperative analgesia; however, these approaches will not normally block pain arising from deep internal organs. Local anaesthetic techniques are particularly useful in day-stay surgery and children. Continuous infusions via a catheter will allow prolonged analgesia. More permanent neural blockade for the control of cancer pain may be achieved by using a neurolytic agent such as absolute alcohol or phenol.

A topical formulation of lidocaine has been marketed for the management of neuropathic pain caused by post-herpetic neuralgia. Up to three plasters may be worn for a 12-h period each day.

Epidural local anaesthetics

Long acting local anaesthetic drugs such as bupivacaine are most effective in relieving pain after major surgery. They work by blocking nerves in the spinal canal serving both superficial and deep tissues, and thus analgesia can be obtained in deep internal organs. Sensory and sympathetic nerves that maintain smooth muscle tone in blood vessels are blocked. As a result, vasodilation can occur, which may result in significant hypotension. Epidural catheters allow continuous infusions and long-term therapy by this route. Adverse effects may include muscle weakness in the area supplied by the nerve and, rarely, infection and haematomas.

Non-opioid analgesics

The pharmacological actions and use of the conventional non-opioids such as paracetamol, aspirin and NSAIDs are well known and will not be discussed further here.

Nefopam is a drug which is chemically related to orphenadrine and diphenhydramine, however, it is neither an opioid, anti-inflammatory drug nor an antihistamine. The mechanism of analgesic action remains unclear. As a non-opioid, it is not associated with the problems of dependence and respiratory depression. The drug has a very high number of dose-related side effects in clinical use that may be linked to its anti-cholinergic actions. Nefopam may be useful in asthmatic patients and in those who are intolerant of NSAIDs.

Adjuvant medication

To be an analgesic, a drug must relieve pain in animal models and give demonstrable and reliable pain relief in patients. Drugs such as the opioids and the NSAIDs clearly are analgesics. In some types of pain, such as cancer pain or neuropathic pain, the addition of non-analgesic drugs to analgesic therapy can enhance pain relief. A list of some adjuvant drugs is given in Table 33.2. It should be remembered that some drugs such as tricyclic antidepressants (TCAs) have intrinsic analgesic activity, perhaps related to their ability to affect 5-HT and noradrenergic neurotransmission.

Table 33.2 Adjuvant drugs used in the treatment of pain

Drug class	Type of pain	Example
Anti-epileptics	Neuropathic pain	Carbamazepine
	Migraine	Sodium valproate
	Cluster headache	Gabapentin
		Pregabalin
		Lamotrigine
Antidepressants	Neuropathic pain	Amitriptyline
	Musculoskeletal pain	Imipramine
		Venlafaxine
		Duloxetine
Intravenous anaesthetic agents	Neuropathic pain	Ketamine
	Burn pain
	Cancer pain
Skeletal muscle relaxants	Muscle spasm	Baclofen
	Spasticity	Dantrolene
	Spasticity	Botulinum toxin (type A)
Steroids	Raised intracranial pressure	Dexamethasone
	Raised intracranial pressure	Prednisolone
	Nerve compression
Antibiotics	Infection	As indicated by culture and sensitivity
Antispasmodics	Colic	Hyoscine butylbromide
Antispasmodics	Smooth muscle spasm	Loperamide
Hormones/hormonal analogues	Malignant bone pain	Calcitonin
	Spinal stenosis	Octreotide
	Intestinal obstruction
Bisphosphonates	Bone pain (caused by cancer or osteoporosis)	Pamidronate (for cancer pain)
Bisphosphonates	Bone pain (caused by cancer or osteoporosis)	Alendronate

Antidepressants

Persistent pain is accompanied frequently by anxiety and depression. Thus, it is not surprising that the use of antidepressants and other psychoactive drugs is a routine component of pain management. There is evidence that some of these drugs have analgesic properties independent of their psychotropic effects.

The TCAs are frequently used for the treatment of persistent pain conditions with and without the anti-epileptics, and there is a substantial body of literature about their analgesic action (McQuay et al., 1996).

The biochemical activity of the TCAs suggests that their main effect is on serotonergic and noradrenergic neurones. The TCAs inhibit the reuptake of the monoamines, 5-HT and/or noradrenaline in neurones found within in the brain and spinal cord. Through a rather complex mechanism, this causes an initial fall in the release of these transmitters followed by a sustained rise in the concentration of neurotransmitter at synapses in the pain neural pathways. This rise usually takes 2–3 weeks to develop. Tricyclic antidepressants are effective analgesics in headache, facial pain, low back pain, arthritis, and, to a lesser degree, cancer pain.

Clinical use of antidepressants in persistent pain

When used in pain management, it is usual to start with a very low TCA dose, for example, amitriptyline 10–25 mg at night and to titrate upwards according to response and adverse effects. Within clinical trials TCA doses have varied considerably but most are lower than used in psychiatry, in the order of amitriptyline 50–75 mg/day. Under specialist supervision higher doses, for example, amitriptyline 150–200 mg/day may be appropriate.

Tricyclic antidepressants have a wide range of adverse effects due to interaction with histamine and muscarinic acetylcholine receptors and these may cause a marked reduction in patient adherence. Newer antidepressant drugs have generally been disappointing from the analgesic perspective. However, much of the research has looked at the selective serotonin reuptake inhibitors (SSRIs). Scientific (Sindrup and Jensen, 1999) and clinical evidence (Sindrup et al., 2005) suggest that a combination of noradrenergic and serotonergic transmission both need to be enhanced for an analgesic effect to be seen. The serotonin/noradrenaline reuptake inhibitors (SNRIs) venlafaxine and duloxetine have effects on both monoamines and appear to possess analgesic activity in neuropathic pain models. A number of antidepressant compounds, including trazodone and mirtazepine, do not act via monoamine reuptake inhibition and do not appear to possess intrinsic analgesic activity. They are effective antidepressants and may have a place in the treatment of co-existing depression but analgesia should be treated separately.

Anti-epileptics

The usefulness of this group of drugs is well established for the treatment of neuropathic pain (McQuay et al., 1995). Conditions which may respond to anti-epileptics include trigeminal neuralgia, glossopharyngeal neuralgia, various neuropathies, lancinating pain arising from conditions such as postherpetic neuralgia and multiple sclerosis and similar pains that may follow amputation or surgery. Several classes of drugs show anti-epileptic activity and these can be broadly classed as sodium channel blockers (carbamazepine, phenytoin), glutamate inhibitors (lamotrigine), voltage gated calcium channel ligands (gabapentin, pregabalin), GABA potentiators (sodium valproate, tiagabine) or drugs showing a mixture of these effects (topiramate). Failure to respond to one particular drug does not indicate that anti-epileptics as a broad class will be ineffective. A drug with a different mechanism of action or combination therapy could be considered.

Anti-epileptics are surprisingly effective in the prophylaxis of migraine and cluster headache. Their mode of action is unclear but both of these conditions are associated with abnormal excitability of certain groups of neurones and the neuronal depression caused by anti-epileptics is probably important.

Ketamine

Ketamine is an intravenous anaesthetic agent with a variety of actions within the CNS. Many of its effects are related to its activity at central glutamate receptors, although it also has actions at certain voltage-gated ion channels and opioid receptors. Low doses of ketamine (0.1–0.3 mg/kg/h via the intravenous route) can produce profound analgesia, even in situations where opioids have been ineffective, such as neuropathic pain. Despite its variable oral availability, oral administration of ketamine can be surprisingly effective (Annetta et al., 2005; Mercadante, 1996). Its usefulness is limited by troublesome psychotropic side effects, although the simultaneous administration of benzodiazepines or antipsychotics can reduce these problems.

Anxiolytics

Benzodiazepines may be used for short-term pain relief in conditions associated with acute muscle spasm and are sometimes prescribed to reduce the anxiety and muscle tension associated with persistent pain conditions. Many authorities believe that they reduce pain tolerance and there is good evidence that they can reduce the effectiveness of opioid analgesics, although the mechanism by which this occurs is unclear. Clonazepam has been used in the management of neuropathic pain. Diazepam can be used to control painful spasticity, due to acute or spinal cord injury, but sedation may be troublesome and baclofen (see below) is probably a more suitable choice.

Antihistamines

These agents were introduced into the management of persistent pain because of their sedative muscle relaxant properties. These actions are non-specific and it is not clear whether the clinical effect is mediated centrally or peripherally. Most clinical studies have been carried out with hydroxyzine, which has shown benefit in acute pain, tension headache and cancer pain, but is not commonly used in current clinical practice.

Skeletal muscle relaxants

Drugs described in this section are used for the relief of muscle spasm or spasticity. It is essential that the underlying cause of the spasticity and any aggravating factors such as pressure sores or infections are treated. Skeletal muscle relaxants usually help spasticity but this may be at the cost of decreased muscle tone elsewhere, which may lead to a decrease in patient mobility, which may make matters worse.

The drug of first choice is probably baclofen, which has a peripheral site of action, working directly on skeletal muscle. Baclofen is a derivative of the inhibitory neurotransmitter GABA and appears to be an agonist at the GABA_B receptor. It is used commonly in the treatment of spasticity caused by multiple sclerosis or other diseases of the spinal cord, especially traumatic lesions.

Dantrolene is an alternative that is effective orally and which may have fewer, but potentially more serious, adverse effects. Its effect is due to a direct action on skeletal muscle and takes several weeks to develop.

The α₂-adrenergic agonist tizanidine has potent muscle relaxant activity and is an alternative to baclofen. It may also have some direct analgesic effects.

Botulinum toxin

The bacterium Clostridium botulinum produces a potent toxin that interferes directly with neuromuscular transmission. Purified preparations of the type A toxin produce long-lasting relaxation of skeletal muscle. The effect often lasts in excess of 3 months and avoids the systemic side effects of agents such as baclofen. Great care must be taken in administering this drug as spread may occur to adjacent muscle groups, producing excessive weakness. Overdosage, with systemic absorption, may lead to generalised muscle weakness and even respiratory failure.

Clonidine

The α-adrenergic agonist clonidine has been shown to produce analgesia, and there is evidence that both morphine and clonidine produce a dose-dependent inhibition of spinal nociceptive transmission that is mediated through different receptors for each drug. This may explain why clonidine has been shown to work synergistically with morphine when given by the intrathecal or epidural routes. Clonidine also appears to be effective when given by other routes or even topically, but may cause severe hypotension by any route.

Cannabinoids

Cannabis has been used as an analgesic for hundreds of years. Problems concerning the legal status of cannabis in most countries have hindered scientific investigation of its analgesic properties. The active ingredient in preparations made from the hemp plant, Cannabis sativa, is δ-9 tetrahydrocannabinol. This compound has analgesic activity in animal models of experimental pain as well as in the clinical situation (Burns and Ineck, 2006). Overall, analgesic activity appears relatively weak and it has not been possible to separate the analgesic activity from the potent psychotropic effects characteristic of these drugs but a commercial preparation is now licensed for the management of spasticity in multiple sclerosis. There may be a clearer analgesic effect in neuropathic pain but the evidence for this remains anecdotal.

Stimulation-produced analgesia

Stimulation-produced analgesia can be used for trauma, postoperative pain, labour pain and various persistent pains.

TENS and acupuncture

TENS machines are portable battery-powered devices that generate a small current to electrodes applied to the skin. The electrodes are placed at the painful site or close to the course of the peripheral nerve innervating the painful area, and the current is increased until paraesthesia is felt at the site of the pain. The current stimulates the large, rapidly conducting (Aβ) fibres which close the gating mechanism in the dorsal horn cells, and this inhibits the small, slowly conducting (Aδ and C) fibres. TENS, in particular, offers the patient a simple, non-invasive, self-controlled method of pain relief with relatively few adverse effects.

Acupuncture also works using a similar manner, although additional mechanisms, including stimulation of endogenous opioid release, may be involved. Acupuncture has been recommended for the treatment of low back pain (National Institute for Health and Clinical Excellence, 2009).

Treatment of selected pain syndromes

Postoperative pain

The majority of patients experience pain following surgery. The site and nature of surgery influences the severity of pain, although individual variation between patients does not allow prediction of the severity of pain by the type of operation.

Apart from the obvious humanitarian benefit of relieving suffering, pain relief is desirable for a number of physiological reasons after surgery or any form of major tissue injury. For example, poor-quality analgesia reduces respiratory function, increases heart rate and blood pressure, and amplifies the stress response to surgery. The use of intermittent and patient-controlled intermittent intravenous opioids injections has been described earlier in this chapter. However, opioids themselves may delay recovery and are associated with adverse events in the postoperative period (Kehlet et al., 1996). It is now common to treat postoperative pain using a ‘multimodal approach’, consisting of paracetamol, NSAIDs, opioids and local anaesthetic blocks or wound infiltration. NSAIDs such as diclofenac and ketorolac are used frequently, but must be used with caution in the postoperative period where there is a possibility of renal stress, such as blood loss, and the normal protective effect of prostaglandins on the kidney will be lost, culminating in acute renal failure. There is no evidence to support the pre-emptive use of either NSAIDs or local anaesthetic techniques, although there is some theoretical and clinical evidence suggesting that opioids given prior to surgery may be more effective than when given postoperatively.

Cancer pain

Cancer and pain are not synonymous. One-third of patients with cancer do not experience severe pain. Of the remaining two-thirds that do, about 88% can be controlled using basic principles of pain management (Scottish Intercollegiate Guidelines Network, 2008). Pain associated with cancer may arise from many different sources, and may exhibit the characteristics of both acute and persistent pain. The mechanisms and sources of cancer pain may change with time and regular assessment is required. Cancer occurs more frequently in the elderly, who may have a larger proportion of painful conditions than the general population. Pain may be arising from these sources too, and these require treatment at the same time.

Cancer pain can be treated both with drugs and other interventional techniques, such as radiotherapy and nerve blocks. Usually, drug treatment is based on the WHO analgesic ladder together with the use of adjuvant analgesics. Opioids are the mainstay for the treatment of cancer pain, although increasingly some clinicians progress from non-opioid drugs to a strong opioid such as morphine, omitting the middle step of the analgesic ladder.

Although this chapter is concerned only with the management of pain, care of the patient with a terminal illness requires management of all aspects of the patient. The Liverpool Care Pathway (LCP) is a resource recommended to promote high-quality care in the last days of life (Ellershaw and Wilkinson, 2003). At a basic level, the LCP is a way of acknowledging that death is imminent and ensuring the patient’s comfort by omitting long-term non-essential medication and anticipatory prescribing in case the patient experiences pain, delirium, vomiting or breathlessness.

Opioid use in cancer pain

Morphine is the first-line opioid used for the management of cancer pain and may be given in immediate or modified release oral formulations. If not tolerated, alternatives such as oxycodone or hydromorphone, both having relatively long half-lives, may be considered. Optimal dosage is determined on an individual basis for each patient by titration against the pain. Patients requiring long-term modified release opioids should have additional oral doses of rapidly acting opioid to act as an ‘escape’ medicine for incident or breakthrough pain. The British National Formulary recommends that the standard dose of a strong opioid for breakthrough pain is one-tenth to one-sixth of the regular 24 hour total daily dose. Methadone should not be used as first-line treatment of cancer pain, but may be useful when alternatives have failed or the patient has experienced intolerable adverse effects.

When the oral route is unavailable, other routes of administration such as the buccal, rectal, transdermal or parenteral (subcutaneous, intravenous) or spinal (epidural or intrathecal) routes may be considered. Syringe drivers or implanted pumps may be used to provide analgesia in cases where conventional opioid delivery is ineffective. Morphine and oxycodone are available for parenteral administration and in the UK, diamorphine is also suitable and readily available. Diamorphine hydrochloride has the advantage of being very water soluble, so a high dose may be given in a small volume, which reduces the frequency of changes of syringes and refills necessary to provide adequate pain relief. The proportion of patients who need an implanted pump for intrathecal drug delivery is extremely small and is confined largely to those who are persistently troubled with unacceptable adverse effects. Such patients may achieve pain relief with lower equivalent opioid doses and have few problems with side effects. Long-term maintenance of indwelling lines and catheters requires training for the patient and specialist expertise from physicians and nursing teams, but excellent long-term results are possible.

Use of adjuvant drugs and treatments for cancer pain

Neuropathic pain is common in cancer. As many as 40% of cancer patients may have a neuropathic component to their pain. Tricyclic antidepressants and anti-epileptic drugs should be introduced early but where these are ineffective, ketamine may have an important role.

Levomepromazine, a phenothiazine with analgesic activity, is a useful alternative when opioids cannot be tolerated. It causes neither constipation nor respiratory depression and has antiemetic and anxiolytic activity. It is sedative, which may be either a virtue or a problem in palliative care.

Corticosteroids are useful in managing certain aspects of acute and persistent cancer pain. They are particularly useful for raised intracranial pressure and for relieving pressure caused by tumours on the spinal cord or peripheral nerves. Dexamethasone is the most commonly used steroid to ameliorate raised intracranial pressure in patients with brain tumours. High steroid doses given for 1 or 2 weeks do not require a reducing-dosage regimen. Also, they may produce a feeling of well-being, increased appetite and weight gain, all beneficial for cancer patients, although these effects are usually transient.

It is essential that underlying causes of pain be treated; therefore, it is appropriate to use antibiotics to treat infections, radiotherapy to reduce tumour bulk or control bone pain, or surgery to achieve fracture fixation or to relieve bowel obstruction in conjunction with antispasmodics such as hyoscine butylbromide.

Specific cancer pain syndromes

Three types of malignant pain are briefly outlined below to indicate various therapeutic approaches.

Cancer of the pancreas

Pain is caused by infiltration of the tumour into the pancreas as well as by obstruction of the bowel and biliary tracts and metastases in the liver. Patients may experience anorexia, nausea, vomiting and diarrhoea, and also are often depressed. Surgery, radiotherapy and chemotherapy may relieve pain for long periods, as does neurolytic blockade of the coeliac plexus. Opioid analgesics are useful and may be administered intravenously or epidurally by either bolus injection or continuous infusion.

Mesothelioma of the lung

Mesothelioma causes pain when the tumour penetrates surrounding tissues such as the pleura, chest wall and nerve plexuses. The WHO analgesic ladder should be used first, but it should be remembered that a NSAID may be beneficial as inflammation is often a component of the chest wall involvement. Adjuvants such as TCAs or steroids may be helpful. As the tumour progresses, nerve blocks or neurosurgery may be necessary, and invasion of the vertebrae can lead to nerve root or spinal cord compression. In the latter case, high dose steroids such as dexamethasone may be given intravenously, but radiotherapy is also useful in reducing the size of the tumour.

Metastatic bone pain

Metastatic bone pain is usually treated with courses of chemotherapy and radiotherapy, but analgesics may also be beneficial. A prostaglandin-like substance has been isolated from bone metastases and therefore NSAIDs and, more recently, bisphosphonates are often used in bone pain. Steroids also interfere with prostaglandin formation and dexamethasone, therefore, has a role, especially where there is nerve root or spinal cord compression.

Neuropathic pain

Neuropathic pain may be defined as ‘pain arising as a direct consequence of a disease or lesion affecting the somatosensory system’ and may occur as a result of pathological damage to nerve fibres in a peripheral nerve or in the CNS (see Table 33.3). Neuropathic pain may be spontaneous in nature (continuous or paroxysmal) or evoked by sensory stimuli. As the underlying aetiology is different to inflammatory types of pain, patients typically present with disturbances in sensory function often describing their pain as tingling, shooting or electric shocks. It is possible for patients to present with pain in the context of sensory loss. Unlike inflammatory pain, neuropathic pain serves no biological advantage and can be described as an illness in its own right.

Table 33.3 Examples of causes of neuropathic pain

Cause of neuropathy	Examples
Trauma	Phantom limb
	Peripheral nerve injury
	Spinal cord injury
	Surgical
Infection/inflammation	Post-herpetic neuralgia
Infection/inflammation	HIV
Compression	Trigeminal neuralgia
Compression	Sciatica
Cancer	Invasion/compression of nerve tissue by tumour
Ischaemia	Post-stroke pain
Ischaemia	Metabolic neuropathies (e.g. diabetic peripheral neuropathy)
Demyelination	Multiple sclerosis
Drugs	Vinca alkaloids
	Ethanol
	Taxols
	Anti-bacterials for TB and HIV

Typically, neuropathic pain does not respond as well to conventional analgesics, such as paracetamol and NSAIDs. Guidelines for the pharmacological management of neuropathic pain in the non-specialist setting have been published (National Institute for Health and Clinical Excellence, 2010).

Specific neuropathic pain syndromes

Postherpetic neuralgia

The pain associated with herpes zoster infection is severe, continuous and often described as burning and lancinating. Antiviral therapy, such as aciclovir, initiated at the first sign of the rash can reduce the duration of the pain, particularly postherpetic pain, which follows the disappearance of the rash. Tricyclic antidepressants such as amitriptyline are the mainstay of treatment, commencing with low doses (e.g. amitriptyline 10–25 mg at night) and gradually increased according to pain relief (usual dose amitriptyline 50–75 mg at night). This may be combined with anti-epileptic drugs if the response is poor or incomplete. Carbamazepine is historically important but newer anti-epileptic drugs, such as gabapentin and pregabalin, are considered first-line therapy and may be better tolerated. One study has demonstrated a significant difference in the incidence, and to a lesser extent the intensity, of pain in patients who received a single epidural methylprednisolone and bupivacaine injection, compared with those who received antiviral therapy and analgesia as ‘standard care’ (van Wijck et al., 2006). However, given the modest clinical effects on acute pain and no effect on the incidence of postherpetic neuralgia, the routine use of epidural local anaesthetic and steroid injection is not widely supported.

Diabetic peripheral polyneuropathy

Nerve damage and neuropathy is one of the long-term complications of diabetes mellitus (see Chapter 44) and is most prevalent in elderly patients with type II diabetes. Often patients describe numbness but also experience a burning sensation on their feet. The sensory loss can result in painless foot ulcers. Tricyclic antidepressants or serotonin noradrenaline reuptake inhibitors (duloxetine or venlafaxine), and anti-epileptics, such as gabapentin and pregabalin, have been demonstrated to be beneficial.

Trigeminal neuralgia

Trigeminal neuralgia presents as abrupt, intense bursts of severe, lancinating pain, provoked by touching sensitive trigger areas on one side of the face. The disorder may spontaneously remit for periods of several weeks or months. Anti-epileptic drugs, particularly carbamazepine, have been used successfully. If drug therapy is ineffective, neurosurgical techniques such as decompression of the fifth cranial nerve may be considered. If surgery is successful, anti-epileptics should be withdrawn gradually afterwards.

Peripheral nerve injury and neuropathy

Damage to, or entrapment of, nerves can cause pain, unpleasant sensations and paraesthesiae. Tricyclic antidepressants and anti-epileptic drugs, such as gabapentin, have been used with some success to treat neuropathic pain (Moore et al., 2011). A neuroma occurs when damaged or severed nerve fibres sprout new small fibres in an attempt to regenerate. Pain develops several weeks after the nerve injury, and is often due to the neuroma growing into scar tissue, causing pain as it is stretched or mobilised. Treatment of neuroma is very difficult and few treatments are successful. Options include surgery and injections of steroid and local anaesthetic agents.

Complex regional pain syndromes

These are an important group of painful conditions that may follow trauma or damage to nerves and are characterised by neuropathic pain, trophic changes and motor dysfunction. The key elements of successful treatment are effective multi-modal analgesia, including drugs with efficacy for neuropathic pain, and aggressive physiotherapy to facilitate a return to normal function. Sympathetic blockade using local anaesthetics may have a therapeutic role.

Back and neck pain

Back pain is one of the commonest reasons for presentation to a medical practitioner. Despite this, the problem is poorly understood. The most practical classification is based on the duration of symptoms (BenDebba et al., 1997). Acute low pain is generally defined as pain that lasts for a few days or weeks. The majority of these problems tend to be self-limiting and resolve spontaneously. Typical treatments include rest, adequate analgesia with paracetamol, combined with a NSAID and/or a weak opioid, and physiotherapy.

Persistent back pain lasts for much longer and progressively leads to a chronic state associated with pain, depression, anxiety and disability. Early intervention is necessary to ensure good functional and vocational outcomes. If a patient is off work for as much as 6 months, then there is a less than 50% chance of them ever returning to work. The likelihood of returning to work falls to less than 25% after 1 year and is almost zero after 2 years. Although pharmacological therapies may aid rehabilitation, other treatment strategies have a greater role to play in the management of persistent back pain. Guidelines for the management of non-specific persistent low back pain have been developed (National Institute for Health and Clinical Excellence, 2009). It is essential for the patient to develop self-management skills, and current recommendations emphasise the importance of using a biopsychosocial approach to manage this problem. Other treatment options include exercise programmes, manual therapy and acupuncture.

Osteoarthritis and rheumatoid arthritis

Pain often is a presenting symptom in osteoarthritis or the inflammatory arthritidies, which include rheumatoid arthritis. The pathophysiology and management of osteoarthritis and rheumatoid arthritis is covered in Chapter 53.

Myofascial pain

Myofascial pain is pain arising from muscles and is associated with stiffness and neuropathic symptoms such as tingling and paraesthesiae. It may occur spontaneously or following trauma, such as whiplash injury. Myofascial pain syndrome is sometimes also termed myositis, fibrositis, myalgia and myofasciitis. Acute muscle injury can be treated using first aid techniques with the application of a cooling spray or ice to reduce inflammation and spasm, followed by passive stretching of the muscle to restore its full range of motion. Injection therapy with local anaesthetic or saline may be used to disrupt sensitive muscle trigger points. Local injections of botulinum toxin have also been shown to be effective where muscle spasm is prolonged and severe. TENS and acupuncture have an important role to play in reducing pain and muscle spasm. Treatment of persistent myofascial syndromes should always include a programme of physical therapy.

Postamputation and phantom limb pain

The majority of amputees suffer significant stump or phantom limb pain for at least a few weeks each year. Pain will be present in the immediate postoperative period in the stump, and this may be caused by muscle spasm, nerve injury and sensitivity of the wound and surrounding skin. As the wound heals, the pain generally subsides. If it does not, the reason may be vascular insufficiency or infection. Pain occurring some number of years after amputation may be caused by changes in the structure of the bones or skin in the stump. Reduction in the thickness of overlying tissue with age may expose nerve endings to increased stimuli or ischaemia. Usually, conventional analgesics are beneficial for stump pain, although sometimes relatively high doses may be required. Tricyclic antidepressants may also be helpful for stump pain, and surgery may be necessary to restore the vascular supply or reduce trauma to nerve endings.

Phantom pain is a referred pain which produces a burning or throbbing sensation, felt in the absent limb. Cramping sensations are caused by muscular spasm in the stump. The patient with phantom limb pain is often anxious, depressed and frightened, all of which exacerbate the pain. Conventional analgesic drugs alone are generally not adequate for phantom pain, but TCAs and anti-epileptic drugs are useful adjuvants. Other therapy which can be effective includes TENS and sympathetic blockade. These patients frequently require management at specialist pain centres.

Headache

Everybody experiences the occasional tension headaches. They are caused by muscle contraction over the neck and scalp. Often they respond to simple analgesics available over-the-counter, such as paracetamol and NSAIDs. They may also respond to TCA drugs given as a single dose at night as well as non-pharmacological treatments, such as TENS. NSAIDs may be indicated if the headache is associated with cervical spondylosis or neck injury.

Migraine

Most migraine attacks respond to simple analgesics such as aspirin or paracetamol. Soluble preparations are best, as gut motility is reduced during a migraine attack and absorption of oral medication may be delayed. Migraine treatment has improved markedly with the development of the triptan drugs such as almotriptan, eletriptan, rizatriptan, sumatriptan, naratriptan and zolmitriptan (Goadsby, 2005). These are 5HT_1B/1D-agonists that will often abort an attack, especially when given by the subcutaneous route. Their vasoconstrictor activity precludes their use in patients with angina or cerebrovascular disease but side effects are less serious than with the ergot derivatives they have replaced.

Prophylactic drug treatment of migraine includes α-adrenergic blockers, anti-epileptics and TCAs. Persistent treatment is undesirable.

Cluster headache

Cluster headache is a disabling condition characterised by severe unilateral head pain occurring in clusters of attacks varying from minutes to hours. It shares some pathological features with migraine and treatment is similar, although high-resolution MRI studies have shown specific anatomical differences in the brains of people with cluster headache. Triptans are effective in acute attacks, as is inhalation of 100% oxygen. Prophylaxis is similar to that of migraine.

Dysmenorrhoea

Dysmenorrhoea is a common cause of pelvic pain in women. NSAIDs are effective as first-line therapy due to their effect on cyclo-oxygenase inhibition but it can be helped also by the prescription of oral contraceptives, since pain is absent in anovulatory cycles. Dysmenorrhoea due to endometriosis may require therapy with androgenic drugs such as danazol or regulators of the gonadotrophins such as norethisterone.

Burn pain

Patients with burns may require a series of painful procedures such as physiotherapy, debridement or skin grafting. Premedication with a strong opioid before the procedure and the use of Entonox® (premixed 50% nitrous oxide and 50% oxygen) may be necessary to control the pain. Regular opioid administration may be useful to prevent the pain induced by movement or touch in the affected area. The anaesthetic drug ketamine (see above) has potent analgesic activity when used in subhypnotic doses. Its short duration of action may be beneficial to reduce the pain of dressing changes or other forms of incident pain. Even with low doses, a significant proportion of patients will experience side effects of dysphoria or hallucinations. These can be treated with benzodiazepines or antipsychotic compounds, such as haloperidol.

A summary of medicine indications and common therapeutic problems associated with analgesic use are presented in Table 33.4.

Table 33.4 Common therapeutic problems

Problem	Solution	Example
Neuropathic pain	Anti-epileptics	Carbamazepine
		Sodium valproate
		Gabapentin
		Lamotrigine
	Antidepressants	Amitriptyline
	Antidepressants	Imipramine
	Intravenous anaesthetic agents	Ketamine
Malignant bone pain	Bisphosphonates	Pamidronate
Malignant bone pain	Bisphosphonates	Calcitonin
Muscle spasm/spasticity	Skeletal muscle relaxants	Baclofen
		Dantrolene
		Botulinum toxin (type A)
Raised intracranial pressure	Corticosteroids	Dexamethasone
Raised intracranial pressure	Corticosteroids	Prednisolone
Nausea with morphine	Antiemetic	Cyclizne
		Droperidol
		Ondansetron
	Use an alternative route of administration	Topical or subcutaneous
Constipation	Determine if drug induced, for example, opioids or tricyclic antidepressant	Co-prescribe laxatives (e.g. docusate sodium and senna)
Antidepressants in patients with ischaemic heart disease	Use a less cardiotoxic antidepressant	Duloxetine, venlafaxine
Drug interactions with carbamazepine	Use an anti-epileptic which does not affect hepatic enzymes	Gabapentin
Renal failure	Morphine accumulates; use lower dose	Fentanyl
	Morphine accumulates; use lower dose	Buprenorphine
	Use a drug which is not eliminated by kidney
Sedation/ impaired cognition	Identify any drug-related causes and adjust dose or stop drug