Abstract
Pain is described as the fifth vital sign, yet its importance is frequently not fully recognised, despite 68 000 000 analgesic prescriptions being dispensed annually. GPs treat pain in the context of a wide spectrum of patient conditions and co-morbidities, recognising potential drug interactions and side-effects. They also factor in the patient’s anxieties, coping strategies, cultural background and previous experiences of pain. It is no wonder that we frequently do not get it right first time. This article discusses the pharmacological action of the major groups of analgesic drugs, considers common pitfalls, and suggests appropriate drug dosing. A titrated multi-modal approach is recommended to target nociceptor pain pathways, and to reduce the side-effects caused by large doses of monotherapy. It discusses the novel use of analgesic agents previously only used for chronic pain. It does not, however, discuss acute-on-chronic pain, drug tolerance, drug addiction or complex pain management.
The GP curriculum and pain management
Agree treatment goals and facilitate supported self-management, especially around pain severity, function and physical activity Understand that reducing pain and disability rather than achieving complete pain relief should be the goal of treatment
Manage distressing symptoms, e.g. nausea, pain, shortness of breath and confusion Describe the conversion of drugs from oral dosage to other appropriate delivery systems
Pain: Acute and chronic
Acute pain is defined as ‘an unpleasant sensory and emotional experience, with actual or potential tissue damage’ (Mersky, 1986). Tissue injury leads to a cellular response: this involves central neuro-humoral and endocrine stimulation and the release of catecholamines and inflammatory mediators, which all trigger the nociceptive pathways. These lead to a coagulopathic state and an impaired immune response (Dray, 1995). Note, however, that pain severity is often poorly correlated with the extent of tissue injury.
Chronic pain is defined as ‘pain lasting longer than three months or past the normal time for tissue healing to occur’ (Mersky, 1986). It affects 25–50% of the population in their lifetime, and is a major cause of disability and poor quality of life (Fornasari, 2014). It is thought that repetitive nociceptive stimulation leads to central and peripheral nerve sensitisation, altering the receptors and their ion channels, as well as affecting the sympathetic nervous system.
The World Health Organization’s analgesic ladder
In 1986, the World Health Organization (WHO) created an analgesic ladder to help patients with cancer pain in the community (WHO, 1986). This stepwise simplified approach has formed the basis of pain management teaching for many years. The pathway has recently been criticised, due to too many patients with acute, severe pain failing to get early adequate analgesia, while it ignores chronic neuropathic pain. Modifications have therefore included other routes of drug administration, the use of regional local anaesthetic techniques, and the addition of analgesic adjuncts. Ultimately, the WHO analgesic ladder should only be used as a starting point to the individual patient’s tailored pain management.
The Oxford League Table of Pain
The Oxford League Table of Pain (OLTP) compares the effectiveness of analgesic drugs against placebo in published trials of patients with moderate to severe postoperative pain (OLTP, 2003). It includes an estimate of the number of patients one would need to treat (NNT) with a given dose of drug for one person to report at least a 50% reduction in the severity of their pain over the subsequent 6 hours. The NNT is commonly more than two, indicating that a single dose of any analgesic is rarely fully effective in the individual patient. Perhaps surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) are more effective than opioids (see Fig. 1), although this may simply reflect their differing duration of action. The table shows that the proportion of patients with 50% pain relief is very similar for those using placebo (18%), codeine 60 mg (15%) and tramadol 50 mg (19%). By contrast, paracetamol 1 g and ibuprofen 400 mg are much more effective, having values of 46% and 55%, respectively.
OLTP of analgesic drugs.
The OLTP is, however, based on single-dose drug administration. Many patients will want a treatment that produces more than a 50% reduction in the severity of their pain. Other issues include: it does not consider drug side-effects, both positive, e.g. synergistic effects, and negative side-effects and the number needed to harm, e.g. constipation or confusion; drug interactions; or the cost of drugs to the NHS. Hence, the choice of analgesic should be tailored to the individual patient.
Simple analgesia
Paracetamol
Number of prescriptions and net item cost for different analgesic drugs as per prescription cost analysis: England 2014.
Source: HSCIC (2015) .
If a standard dose of paracetamol of 1 g is given to patients whose weight is above 50 kg (at a dose of 20 mg/kg) every 4 to 6 hours, 46% can expect at least a 50% reduction in their pain severity (Fig. 2). Dosages should be reduced to avoid toxicity in patients with liver or renal failure, rapid weight loss, and hypoalbuminaemia (as the active free fraction of the drug is greater). Paracetamol works synergistically with NSAIDs, and has been shown to reduce the total amount of morphine that patients require, especially when prescribed in combination with other analgesic drugs.
Comparison of effectiveness of paracetamol and codeine at varying doses.
NSAIDs
NSAIDs are highly efficacious and have a significant opioid-sparing effect. Their long-term use has been questioned in recent years, due to their side-effect profile, including gastritis and exacerbations of renal and cardiac disease. They work by inhibiting cyclooxygenase isoenzymes 1 and 2 (COX inhibitors), decreasing the production of key inflammatory mediators: prostacyclin, prostaglandin and thromboxane. These inflammatory mediators are released in response to cell damage and are the key to peripheral and central pain transmission and modulation. The COX isoenzymes have many roles throughout the body, including protecting the intestinal mucosa, preserving renal blood flow, as well as influencing activation and function of platelets. Newer NSAIDs, COX 2 receptor inhibitors, e.g. rofecoxib, celecoxib and parecoxib, significantly increase patients’ cardiovascular and cerebrovascular risk, and as a result are not recommended for regular long-term use in patients with cardiac disease (Chou et al., 2015). For those patients who can tolerate the drug, NSAIDs can reduce morphine requirements by between 30 and 50%, for example, when used in day case surgery (Frampton & Quinlan, 2009).
Figure 3 shows the dose response curves for ibuprofen and tramadol. When compared to other analgesics, such as 10 mg intramuscular morphine (NNT: 2.9), high-dose ibuprofen produces at least 50% pain relief in 86% of patients (NNT: 1.7) (OLTP, 2003). This extra benefit of ibuprofen is not too surprising, as these large doses can be expected to last longer than morphine (6–8 hours, compared with 3–4 hours for a single dose of intramuscular morphine). However, this comes at a greater risk of side-effects.
Dose response curve for ibuprofen and tramadol.
The risk-to-benefit ratio for the use of NSAIDs must be considered in every patient, especially those at high risk of adverse effects, such as patients greater than 65 years in age, and those with serious co-morbidities, including cardiovascular, hepatic and renal disorders. Patients require mucosal protection for courses longer than 2 weeks, or if using high doses. Care must be taken when prescribing them to the elderly, due to their association with renal failure, exacerbating cardiovascular and cerebrovascular disease.
Case study 1. Osteoarthritis.
A 58-year-old gentlemen presents with pain in his knees and hands. He is diagnosed with osteoarthritis of these joints.
Prior to starting pharmacological agents, ensure appropriate patient information is provided with advice on activity, exercise and weight loss.
Add in weak opioids, such as codeine.
Intra articular corticosteroids should be considered as an adjunct to steps 1 to 3 for the relief of moderate to severe osteoarthritic pain.
(For further information see RCGP e-learning module: Management of chronic pain in adults).
Source: NICE (2012a) .
NSAID gels
Topical NSAIDs, such as ibuprofen, diclofenac, salicylate and ketorolac, are now recommended as first-line treatment for osteoarthritis affecting the hands and knees (National Institute for Health and Clinical Excellence (NICE), 2014). They work by infiltrating inflamed tissue and inhibiting prostaglandin and cytokine release. As they are not absorbed in large quantities into the circulation, they cause fewer of the gastrointestinal, kidney hypo-perfusion, and coagulation issues that are associated with oral NSAIDs.
‘Weak’ opioids
Codeine
Codeine is a naturally occurring opioid, which is metabolised to morphine by the enzyme cytochrome CYP2D6. Unfortunately, 9% of Caucasians lack this enzyme and are unable to convert codeine into morphine (Nair, 2013). Many more patients are either slow to metabolise or incompletely metabolise codeine, as there is considerable variation in this cytochrome’s allele. Conversely, super-metabolisers, who have an exaggerated response to even a small dose of codeine, leading to harmful side-effects and potential respiratory depression, constitute 0.5–2% of the population (Nair, 2013). This led to a government alert in 2007 on the use of codeine in breastfeeding mothers, due to the potential risk of respiratory depression in the neonate from the morphine in breast milk (Joint Formulary Committee, 2016).
The dose response curve for codeine, shown in Fig. 2, indicates that only 15% of patients given 60 mg of codeine can expect to get a 50% reduction in pain: so it is less effective than placebo (OLTP, 2003). However, the addition of 1 g of paracetamol increases this to 57% of patients.
Tramadol
Tramadol, an analogue of codeine, is thought to act on both the opioid Mu receptor and by inhibition of norepinephrine and serotonin reuptake. Its multi-receptor action significantly increases the side-effect profile. Unfortunately, some 7% of the population do not have the enzyme required to convert tramadol into its active metabolite, and so will not get any analgesic benefit (Vellucci, Mediati, & Ballerini, 2014). Tramadol reduces the seizure threshold, so care must be taken with its use in patients with epilepsy, and in those with drug or alcohol addiction.
Although there is a dose-dependent increase in efficacy with tramadol (see Fig. 3), even at a dose of 150 mg, it is less effective than 400 mg of ibuprofen (OLTP, 2003). At this dose, side-effects, e.g. dizziness, lethargy, nausea and vomiting, are almost universal. The slow titration of tramadol has been shown to improve patient tolerance, whereas lowering doses in elderly patients and in those with liver and renal disease, reduces toxicity.
Strong opioids
Opioids produce pain relief by activating centrally acting mu (μ), kappa (κ) and delta (δ) receptors. Unfortunately, receptor activation also contributes to undesirable side-effects, such as constipation, sedation, nausea and vomiting. The affinity of opioids for these different receptors, and their rate of metabolism, will vary between patients, which helps explain the variation in clinical effectiveness and side-effects seen in clinical practice. Each patient must balance the analgesic effect against unwanted side-effects, as well as the risk of addiction and toxicity.
Morphine sulphate
Morphine sulphate is a full mu receptor agonist, available in both immediate and sustained-release forms, used in both acute and chronic pain management. Mu receptor activation in the bowel delays gastric emptying, slows gut motility, and increases the risk of vomiting and constipation (Mowat & Johnson, 2013).
Oxycodone
Oxycodone also acts on mu and kappa receptors, but is said to produce fewer side-effects than other opioids. It is available in an immediate-release preparation, with peak plasma levels at 1 hour following ingestion, although its analgesic effect starts within 15 minutes. The sustained-release preparation begins to work about an hour after ingestion, reaching peak plasma levels at 3 hours. It is metabolised by cytochrome p450 enzymes in the liver, so drug interactions are a risk. A dose of 6.7 mg of oxycodone is equivalent to 10 mg of morphine, so there is a risk of over-dosage if a direct switch is made between morphine and oxycodone (Shaheen, Walsh, Lasheen, Davis, & Lagman, 2009). The faster onset of action, increased potency and fewer side-effects of oxycodone (compared with morphine) have led to concerns about its addictive potential in the US and Canada. Targinact® is a combination of oxycodone and naloxone (a specific mu receptor antagonist that is not centrally absorbed, but acts locally in the bowel). This reduces the severity of constipation in patients requiring long-term opioid use
Adjuvant agents
Anti-depressants have long been used for their analgesic effects, the most common being tricyclic anti-depressants (TCA), e.g. amitriptyline or duloxetine, a serotonin-nordrenaline reuptake inhibitor (SNRI). Similarly, anticonvulsants, e.g. gabapentin and pregabalin are prescribed primarily for chronic and neuropathic pain states. Both anti-depressants and anticonvulsants are increasingly being used for their opioid-sparing effect, as part of a multi-modal approach for short- and long-term pain management.
Following acute pain, repeated stimulation of peripheral and central nociceptors lowers their action potential threshold. This sensitization of the nerves, along with neurogenic inflammation from cytokines, histamine, bradykinin and serotonin, all play a role in the development of chronic and neuropathic pain states (Neil, 2011). TCAs and SNRIs act on sodium and calcium channels to reduce this sensitization, through prevention of serotonin and norepinephrine reuptake at the nerve terminals in the descending inhibitory pain pathways (Sindrup, Otto, Finnerup, & Jensen, 2005). The anticonvulsants also work by reducing the sensitization of central nerves following repeated nociceptor stimulation.
TCAs: Amitriptyline
Originally used as an anti-depressant, amitriptyline has been shown to be efficacious at much lower doses in chronic and neuropathic pain. It is also effective in migraine prophylaxis, diabetic neuropathy, atypical facial pain and fibromyalgia. Amitriptyline produces at least a 50% pain relief within 3–6 weeks of starting it compared with placebo, with a NNT of 2.3 in post herpetic neuralgia, 2.8 in atypical facial pain and 3.0 in diabetic neuropathy. In comparison with newer anti-depressants, such as paroxetine (NNT 5) and fluoxetine (NNT 15.3), amitriptyline is more effective at reducing pain levels, but unfortunately it is associated with more cholinergic side-effects (OLTP, 2003). These include dry mouth, dizziness, headache, mood disturbances and weight gain. If taken in the evening before bed, the common side-effect of drowsiness can be used to assist with sleep. They are contraindicated in patients with known cardiac disease or arrhythmias, as they can cause orthostatic hypotension and sinus tachycardia. Amitriptyline also increases the risk of seizures if taken with tramadol. It has a high risk of toxicity in overdose, with symptoms of tachycardia, arrhythmias, seizures, drowsiness and coma (Joint Formulary Committee, 2016).
SNRIs: Duloxetine
In 2014, a Cochrane review concluded that duloxetine was helpful in the treatment of diabetic neuropathy and fibromyalgia; although less effective than TCAs and opioids, it was better tolerated with fewer side-effects.
Nausea is the most common side-effect, followed by dizziness, somnolence, dry mouth, headaches and low libido. Duloxetine is also potentially hepatotoxic (raised transaminases), and causes mydriasis (pupillary dilatation), so should be avoided in patients with pre-existing liver disease or glaucoma. Unfortunately, duloxetine is associated with a twofold increase in suicide risk in patients under 25 years in age. Patients on duloxetine should have their blood pressure, liver function enzymes and full blood count (to exclude agranulocytosis) regularly monitored. If being discontinued, it should be withdrawn gradually, as abrupt stopping can cause irritability, dizziness, anxiety and confusion (Lunn, Hughes, & Wiffen, 2014).
Gabapentin
Initially designed as an anticonvulsant, gabapentin has since been used for the treatment of neuropathic pain, restless legs syndrome, diabetic neuropathy and post herpetic neuralgia. It is thought to work by blocking calcium channel influx in the spinal cord dorsal horn and by preventing new synapse formation in the central nervous system, which is the pathophysiology seen in chronic pain development.
Gabapentin is less well tolerated than pregabalin, in terms of side-effects such as dizziness, sexual dysfunction, weight gain and drowsiness. However, as gabapentin is a tenth of the cost of pregabalin, it should generally be prescribed as a first-line agent (Table 1, HSCIC, 2015). A meta-analysis in 2010 showed that there was an increase in risk of suicide with gabapentin, especially when used in conjunction with other anticonvulsants (Andersohn, Schade, Willich, & Garbe, 2010).
A starting dose of 100 mg three times a day can be increased up to 3600 mg per day if tolerated. Patients are commonly prescribed a larger dose in the evening to assist with sleeping.
Pregabalin
Pregabalin is indicated for use in the management of fibromyalgia, headaches, generalised anxiety and diabetic neuropathy. Dose-dependent side-effects, such as dizziness and drowsiness occur in 15–45% of patients with doses greater than 600 mg per day. Approximately 18–28% of patients discontinue their drug regime due to adverse effects (Scottish Intercollegiate Guidelines Network (SIGN), 2013). The dose should be reduced in patients with renal failure, as like gabapentin, it is excreted unchanged and can accumulate leading to toxic concentrations. Sudden withdrawal can lead to a discontinuation syndrome, so wean the drug slowly over a couple of weeks. It is generally started at 150 mg per day in two to three divided doses, increasing up to a total of 600 mg per day, with slow titration over a few weeks, depending on patient tolerance (Joint Formulary Committee, 2016).
Case study 2. Sciatica.
A 38-year-old lady with a body mass index of 38 kg/m2 presents with acute worsening of her sciatica. Prior to starting pharmacological agents, ensure appropriate patient information is provided on self-help measures, including keeping active.
If the patient has muscle spasm: add benzodiazepine as an antispasmodic, e.g. 2 mg diazepam three times a day for 5 days if not contraindicated.
Source: NICE (2011) .
Analgesic patches
Transdermal medications, such as fentanyl and buprenorphine patches, are absorbed slowly into the blood stream at a steady state, where they are then distributed throughout the body. They are available in an array of strengths and can be used as part of a multi-modal approach.
Lidocaine
Typically used in neuropathic pain, 5% lidocaine patches can be applied over a painful area to reduce nociceptor transmission, without causing a decrease in cutaneous sensation. Lidocaine, a potent local anaesthetic, is absorbed through the skin and spreads around the underlying nerves. The patches should be applied for 12 hours per day and are most commonly given for 2–4 weeks only. They must be removed for at least one day a week to reduce central absorption. Due to the low absorption into the bloodstream, they are very safe with rare systemic side-effects, but are expensive.
Fentanyl
In the past, fentanyl patches were only used in patients with chronic pain secondary to cancer, who had stable opioid requirements. More recently, their use in chronic neuropathic pain has increased. They cost significantly more than slow-release oral morphine (see Table 1) and are generally reserved for use in patients with difficulty swallowing, vomiting or renal failure, in whom oral opioids are not appropriate (HSCIC, 2015). Multiple strengths ranging from 12 micrograms/hour patches up to a maximum of 100 micrograms/hour are frequently prescribed with an oral fast-acting morphine for breakthrough pain. Fentanyl is a pure Mu agonist, the patches begins to show clinical effect within 12–24 hours of application and have to be reapplied every 72 hours, where the dose can be increased if necessary. They should not be prescribed to patients who are opioid-naïve, due to the risk of respiratory depression.
Studies comparing trans-dermal fentanyl patches for patients with cancerous and non-cancerous pain have shown it has equal efficacy as slow-release oral morphine in pain management (Vithlani & Baranidharen, 2010). Trans-dermal fentanyl has similar side-effects to slow-release morphine, except for a reduced incidence of constipation. When transferring from one opioid to another, it is best to underestimate the dose required to minimise side-effects from the new agent.
Case study 3. Cancer pain.
A 54-year-old man presents with a recent diagnosis of pancreatic cancer and severe abdominal pain. He has no co-morbidities or drug allergies.
Anti-emetics and laxatives may be required Omit this step if patient is in severe pain and clinically appropriate
Conversion of sustained oral morphine to transdermal patch is approximately 4:1. If the patients 24 hour daily opioid requirement is 50 mg of oral sustained morphine this equates to a 12 microgram/hour fentanyl patch
(For further information see RCGP e-learning module: Safe and effective prescribing of strong opioids for pain in palliative care.)
Source: NICE (2012b) .
Buprenorphine
Similar to fentanyl, buprenorphine patches should only be used when sustained-release oral morphine is not appropriate. Patches come in a variety of strengths ranging from 5 micrograms/hour up to 70 micrograms/hour, with a maximum dose of 140 micrograms/hour. They are generally used in patients with cancer and chronic stable pain, but their use by pain specialists in neuropathic pain is increasing. Buprenorphine is a semi-synthetic drug that produces its analgesic effects through its partial agonism of Mu receptors. Counterintuitively, it is also an antagonist of both delta and kappa receptors, but this does not reduce its analgesic properties when used independently or in combination with other opioids (Pergolizzi, 2010).
Buprenorphine patches take up to 24 hours to show significant clinical effect and need changing every 7 days. Once the patch is removed, it takes up to 30 hours for 50% of the buprenorphine to be excreted. Conversion from sustained-release oral morphine to buprenorphine patches can be challenging, as absorption rates can differ greatly between patients. However, a 20 microgram/hour patch is roughly equal to 30 mg of oral morphine per day (NICE, 2012c). Buprenorphine and fentanyl patches are safe for use in patients with renal dysfunction, but have varying side-effect profiles with localised skin reactions, such as pruritus and erythema occurring more commonly with fentanyl (Vithlani & Baranidharan, 2010).
Conclusions
Common analgesic drug dosing, side-effects and cautions.
Source: Joint Formulary Committee (2016) .
Key points
A multi-modal approach provides optimum pain relief with reduced side-effects Increasing the dose of a drug does not necessarily mean an increase in pain relief, as side-effects increase Chronic morphine use increases the risk of myocardial infarction and fractures in those over 60 years of age Refer to pain specialist for difficult to manage acute or chronic pain
Footnotes
Acknowledgement
We would like to thank Dr Duncan Shrewsbury for his help with the writing of this article under the InnovAiT ‘buddy’ scheme.