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March 2007: Achieving optimum pain control in terminally ill patients at home

How is breakthrough pain best managed?

When should you use a syringe driver?

How do you calculate doses when switching opioids?

How is breakthrough pain best managed?

When should you use a syringe driver?

How do you calculate doses when switching opioids?

The WHO analgesic ladder is well established in the management of cancer pain and has been incorporated into the SIGN guidelines for the control of pain in patients with cancer.1 The SIGN guidelines are used across the UK and outline the basic knowledge expected of a non-palliative care specialist. However, the guidelines are not always implemented correctly. Furthermore, they were published in June 2000 and since that time there have been further developments in the use of alternative opioids. Consequently, some of the more complex situations that GPs encounter, such as the management of incident pain and opioid toxicity, are not covered in depth by the guidelines.

The following case histories illustrate complex but common clinical situations and discuss the management options.

Patient 1: uncontrolled pain at the end of life

A 58-year-old man with lung cancer and bone metastases has had his pain controlled for two months with a transdermal 75µg/h fentanyl patch. Over the past few weeks he has become weaker and is now bedbound, with increasing pain from a thoracic vertebral metastasis at T6. For the past week he has been taking 40mg normal-release morphine twice a day for breakthrough pain. Swallowing is now becoming difficult. He is near to death, with an acute exacerbation of chronic pain, and is having difficulty in swallowing even liquids.

Discussion

This man has acute on chronic pain and is in the terminal stages of his illness. Clearly there is a need for increased analgesia. Altering the fentanyl dose at this stage will produce a relatively slow change in plasma fentanyl levels,2 hence it is not suited to rapid titration aimed at restoring pain control. The easiest and most effective way to achieve pain control is to supplement the patch using continuous subcutaneous infusion (CSCI) of opioid via a syringe driver. An infusion is therefore set up with diamorphine.

The dose of SC diamorphine is calculated from the amount of breakthrough morphine taken in the preceding 24 hours (see box 1, attached). However, even with this amount of breakthrough analgesia pain was still present, so you wish to increase the dose of diamorphine by an extra 30 per cent (see box 1, attached).

You also increase the breakthrough dose. To calculate this you need to take account of the newly calculated SC diamorphine dose over 24 hours plus the 75µg/h fentanyl patch (see box 2, attached).

Your patient settles rapidly on the new doses and remains comfortable until his death three days later.

Patient 2: when to use a syringe driver

A 44-year-old woman with metastatic breast cancer is nearing the end of her life. Her pain control has been good on modified-release morphine 60mg every 12 hours and 20mg normal-release morphine for breakthrough pain. She has required two doses of breakthrough analgesic each day for the past two days. She is having difficulty in swallowing and you wish to maintain good analgesia. She agrees to convert to a syringe driver with CSCI diamorphine replacing the oral opioids.

You prescribe 40mg of diamorphine SC over 24 hours via the syringe driver (see box 3, attached). You check the diluent, which is sterile water. The district nurse commences the infusion and changes the syringe daily.

Pain control is maintained. Your patient dies at home six days later and the family are pleased that she was able to spend her last days at home.

Discussion

41136109The oral route is the route of choice for analgesics. If this is not possible, avoid intramuscular injection and use a syringe driver to administer analgesic subcutaneously (see table 1, above). It is important to be aware of oral to SC conversions of opioid doses (see table 2, attached).

Patient 3: breakthrough pain

A 63-year-old woman with metastatic lung cancer presents to you complaining of chest pain. She has already received all available treatment options and her management is purely palliative. She describes episodes of severe dull pain in her posterior chest that occur spontaneously without any specific precipitants. She has had this pain from the time of diagnosis and it has responded well to morphine. She is currently on sustained-release morphine sulphate 30mg twice daily, with 10mg normal-release morphine sulphate for breakthrough pain. Over the past few days she has been taking this four times a day. It is effective in dulling the pain from a score of 9/10 on a numerical rating scale to 4/10, but it takes about an hour to work and the effect only seems to last for about three hours.

Discussion

This patient needs to have her opioid dose increased. You ascertain that she is not suffering any side-effects from the morphine other than constipation. You increase her regular morphine dose to 50mg twice daily, to include her breakthrough requirements for the previous 24 hours, which are 40mg. Her breakthrough dose is also increased in keeping with this to 15mg, which is approximately one-sixth of the regular 24-hour opioid dose. You also prescribe a stimulant laxative with a softener and advise her to take this every night to treat her constipation and prevent it recurring. When you review her a week later she only requires her breakthrough dose once or occasionally twice a day, and finds the increased dose more effective on these occasions.

Patient 4: incident pain

A 42-year-old man with known prostate cancer and bone metastases comes to the surgery complaining of increasing pain in his right leg. He is known to have a lytic lesion in this area and has had radiotherapy for pain control in the past. He is on sustained-release morphine sulphate 30mg twice daily, with normal-release morphine sulphate 10 mg for breakthrough pain, an NSAID, paracetamol and a laxative.

On questioning you ascertain that his pain is related to movement and he has become quite restricted in his activities as a result. He is comfortable at rest and gets a good night's sleep. Clinical examination reveals local tenderness over the greater trochanter.

Discussion

This is a typical description of incident pain, which is pain caused by an action of the patient such as movement.3 It is a particular problem, therefore, for patients with bone metastases. Increasing the dose of the regular sustained-release opioid sufficiently to overcome episodes of incident pain carries the risk of causing side-effects, such as excessive drowsiness, between episodes of pain. As this pain is to a certain degree predictable, it is best managed with the prophylactic use of a normal-release opioid.

You prescribe oral transmucosal fentanyl citrate (OTFC), which is licensed for the treatment of breakthrough pain. Fentanyl is rapidly absorbed from the buccal mucosa, with onset of pain relief in five to ten minutes and a peak plasma level in 20 minutes. Duration of action is about two hours.4 These characteristics make it suitable for the treatment of incident pain.

The fentanyl is contained within a lozenge on a stick. The lozenge should be rubbed against the buccal mucosa for 15 minutes to allow the fentanyl to dissolve in the saliva and diffuse across the mucosa. It should not be sucked.

If side-effects occur before the lozenge has dissolved, the patient can simply remove the lozenge and dispose of any remaining by dissolving it down the sink.

Unlike other opioids, where the breakthrough dose is one-sixth of the 24-hour baseline opioid dose, there is no relationship between the baseline opioid dose and the dose of OTFC required to manage breakthrough pain.5 You therefore need to titrate the dose, starting with 200µg or 400µg OTFC, bearing in mind that, on average, patients require 600µg for effective analgesia (see figure 1, attached).

With this method, if a lozenge is ineffective within 15 minutes, a second lozenge should be tried straight away. If this too is ineffective, the patient's usual breakthrough analgesic should be taken and a stronger OTFC lozenge tried at the next episode of breakthrough pain. Because of the need to titrate in this way, it is wise to prescribe a small number of lozenges in the first instance.

OTFC is best suited to patients who are cognitively alert. A dry mouth can delay the rate that the lozenge dissolves, so patients can be advised to wet their mouth with water before they take it and while they are taking it.

You arrange plain X-rays of the man's femur to rule out a pathological fracture. Review by his oncologist may be indicated for consideration of further radiotherapy or regular bisphosphonates. You also consider orthopaedic review regarding the possibility of prophylactic pinning of his femur.

Patient 5: adjuvant analgesics

A 72-year-old man with metastatic adenocarcinoma of the caecum requests a house call. In the past few weeks he has been diagnosed with disease progression, and in addition to his known liver metastases he has a large lymph node mass involving his coeliac plexus. He is complaining of excruciating abdominal pain.

On closer questioning he describes a severe gnawing pain in his upper abdomen, a dull aching pain in his right side, which is worse when he stands up and eased by lying on his right side, sharp, severe gripping pains in his abdomen associated with needing to pass wind and a similar pain localised to the suprapubic area, particularly when he tries to urinate. His bowels are moving and he has no dysuria. A recent midstream urine specimen was negative.

You have titrated his sustained-release morphine sulphate to 30mg twice daily with 10mg normal-release morphine for breakthrough pain. Although this has had some benefit, he still describes gnawing epigastric pain and gripping pain associated with passing flatus and micturition. However, in the past he has developed opioid toxicity on higher doses so is reluctant to accept a further increase.

Discussion

This case illustrates the importance of taking a careful pain history, as patients often have more than one pain and these may have different aetiologies. Based on the descriptions of pain and the scan results, you diagnose neuropathic pain from coeliac plexus involvement, liver capsule stretch pain from the hepatic metastases, and bowel and bladder spasms. You add in gabapentin for the neuropathic element and titrate the dose from 100mg tds to 200mg tds to 300mg tds over three days. You also prescribe hyoscine butylbromide 20mg qds for its antispasmodic effect. You start dexamethasone 2mg bd to help with the liver pain, and ensure that he takes a proton pump inhibitor to provide gastric protection from the steroid.

On review the next day he is much more comfortable and continues to improve over the coming week. Using adjuvants in this way allows you to keep his opioid dose to a minimum, thereby avoiding the risk of side-effects.

Patient 6: terminal agitation and opioid toxicity

You are called to see a 72-year-old man with advanced lung cancer. He has been deteriorating for some time and is thought to be in the terminal stages of his illness. He is now taking very little fluids and almost no food, and administering his medication is becoming a struggle. Three days ago you stopped his oral morphine and started him on an SC infusion of diamorphine. His pain control has been good, but his family are now concerned as he seems to be very sleepy and confused and is becoming restless. He moans as if in pain when moved and you note that he is ‘jerky'. His family are worried that he may be in pain and needs an increase in the dose of diamorphine.

Discussion

Although ‘terminal agitation' may be caused by psychological or spiritual distress, it is often a manifestation of delirium. Frequent precipitants include infection, metabolic derangement and drugs, such as opioids, which give rise to opioid toxicity.

The challenge for the GP in managing delirium at the end of life lies in identifying and treating, as appropriate, any reversible causes, and finding a balance between symptom control and excessive sedation of the patient. A careful history from the patient, if possible, and the family is paramount. Clinical examination should include a check

for signs of dehydration, metabolic disturbance such as asterixis, pyrexia, organ failure and infection. A dehydrated patient with possible renal impairment is more likely to develop opioid toxicity. Typical signs of this are given in table 3, attached.

Opioid toxicity may produce hyperalgesia and allodynia: patients complain that they are ‘sore all over', with any touch being painful. Failure to recognise this rare phenomenon may lead to further escalation of the opioid dose and worsening of the problem.

Opioid toxicity responds well to a reduction in opioid dose of about one-third. Rehydration, possibly with SC fluids, will often improve toxicity if it is associated with dehydration and mild renal impairment. If the patient is in pain, adjuvants may help to reduce the need for opioids. Conversely, pain may improve once the toxicity resolves.

Haloperidol is the treatment of choice for delirium6 and is particularly useful for treating vivid distressing dreams and hallucinations. Haloperidol 2.5–5mg can be added to the SC infusion for symptomatic relief.

If these measures fail, switching to an alternative opioid that the patient may be more responsive to may improve things, as discussed earlier. On conversion, a reduction of one-third is advised to avoid side-effects from the new opioid.

Early review after switching is recommended to allow assessment of efficacy and side-effects.

Patient 7: opioid switching for unacceptable side-effects

A 31-year-old woman with metastatic carcinoma of the lower oesophagus is on modified-release morphine 100mg every 12 hours for severe epigastric lower sternal pain. She has 30mg normal-release morphine sulphate for breakthrough pain. Her pain worsens and she takes breakthrough analgesic four to six times a day (4 x 30mg = 120 mg/24 hours extra breakthrough).

Her MST is increased to 160mg every 12 hours and correspondingly her breakthrough analgesic dose is increased to 50mg. She becomes sleepy and a little confused. She dislikes this as she has to be alert for her three children. Usually after a dose increase any sleepiness and mental clouding resolve within 48 hours, but in her case symptoms persist even after 72 hours. However, as she still requires one or two breakthrough doses a day, you do not want to reduce the dose.

After discussion with the patient, you decide to switch her opioid to oxycodone. The conversion is half the oral morphine dose per 24 hours. Hence, the dose of modified-release oxycodone is 80mg every 12 hours and the breakthrough oxycodone dose is 25mg. (Oral oxycodone is twice as potent as morphine.)

Your patient does well on this. But after three months her pain worsens and the dose of modified-release oxycodone is now 200mg every 12 hours, with breakthrough oxycodone 60mg. The pain is fairly well controlled at this dose, with two breakthrough doses per day. However, she again becomes very sleepy, and is experiencing slight nausea and having difficulty concentrating. You decide to switch opioids again. You choose hydromorphone. Hydromorphone is 7.5 times as potent as morphine (so 7.5mg morphine is equivalent to 1mg hydromorphone), hence the new dose of opioid is 50mg modified-release hydromorphone every 12 hours with a breakthrough dose of 16mg (see box 4, attached).

Discussion

This case illustrates reaching the ‘therapeutic limit' of an opioid. When titrating opioids, the dose can be increased until either pain control is achieved or unacceptable side-effects develop. When the latter occurs, and if other methods for managing the side-effects as outlined in the SIGN guidelines are not effective, switching to an alternative opioid is usually successful in improving pain control while decreasing side-effects.7

Currently, there are several opioids available on the UK market, including morphine, oxycodone, hydromorphone, fentanyl, methadone and buprenorphine. These vary in their physiochemical properties and there appears to be genetic polymorphism in the opioid receptors found in the population. These two characteristics result in a variation in intensity of analgesic effect and differences in the degree of severity of opioid side-effects. The side-effect profile is fairly constant and standard for all opioids – it is the degree of expression that varies. Therefore individuals are likely to tolerate some opioids better than others. Unfortunately, at present one cannot predict who will tolerate which opioid best.

When switching between opioids, conversion tables should be consulted to calculate the approximate equi-analgesic dose (see table 4, attached). It is safest to reduce the dose of the new opioid by one-third to allow for the fact that the patient will have developed some tolerance to the new opioid through previous opioid exposure.

Box 1: Calculate the dose of diamorphine for 24 hours' continuous SC infusion (CSCI) Box 2: Calculate the dose of breakthrough diamorphine when on a fentanyl patch and continuous SC infusion (CSCI) diamorphine Box 3: Calculate the dose of diamorphine for 24 hours' continuous SC infusion (CSCI) Table 2: Conversion table for oral to SC doses of opioids Figure 1: Titration of oral transmucosal fentanyl citrate for incident pain Table 3: Detecting opioid toxicity Box 4: Calculation of hydromorphone dose Table 4: Opioid conversion table pain_tab1 pain key points Key points Authors

Dr Rachel Thorp
MB BCh BAO, MICGP
consultant in palliative medicine, Ardgowan Hospice, Greenock

Professor John Welsh
BSc (Hons) MB ChB, FRCP, Professor of Palliative Medicine, Glasgow University, Beatson Oncology Centre, Western Infirmary, Glasgow

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