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.

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.