6a The management of pain

I think the simplest and probably the best definition of pain is what the patient says hurts. I think that they may be expressing a very multi-faceted thing. They may have physical, psychological, family, social and spiritual things all wound up in this one whole experience. But I think we should believe people and once you believe somebody you can begin to understand, and perhaps tease out the various elements that are making up the pain.

Cicely Saunders

The Specificity Theory of pain, which was proposed by René Descartes in the sixteenth century, is one of the original pain theories. It states that pain intensity relates directly to the amount of associated tissue injury. Its unidimensional approach to pain implies that 100% of pain is treatable by analgesics.

Dr Henry Beecher recognized the limitations of this theory in the Second World War when he observed that only one out of three soldiers carried into a combat hospital complained of enough pain to require morphine.¹ He noted that a mismatch between pain intensity and injury severity occurs in certain situations.

Melzack and Wall proposed the Gate Control Theory of pain in 1965, and suggested that a spinal cord mechanism existed that regulated the transmission of pain sensations between the periphery and the brain.² The theory shifted attention away from the peripheral source of injury towards the spinal cord and brain. It provided the first physiological mechanism for psychological interventions to minimize pain (e.g. distraction or relaxation).

Following on from their work an increasingly multidimensional approach to pain was adopted, and clinicians now recognize that pain perception is governed by a multitude of factors (the Neuromatrix Theory of pain).³

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

International Association for the Study of Pain

Dame Cicely Saunders also recognized that other important factors can influence the pain experience. In parallel with the work of others, she developed the concept of ‘total pain’ from her understanding that the origins of pain may be:

The concept of total pain has become a central tenet of palliative care practice. It recognizes that cancer pain is often a complex, chronic pain with multiple, coexisting causes. Effective management of cancer pain requires a multidisciplinary approach that addresses the patient’s concerns and fears, as well as treating the physical aspects of pain. As a result, the provision of analgesics should be combined with the provision of emotional, social and spiritual supports.

One patient in particular, a lady whose name should be recorded, a Mrs. Hinson, there were days that I remember saying to her, ‘Tell me about your pain,‘ and without any more prompting from me, she went on to say, ‘Well doctor, it began in my back, but now it seems that all of me is wrong.‘ And she gave a description about her symptoms. And then she went on to say, ‘I could have cried for the pills and the injections, but I knew that I mustn’t, the world seemed to be against me, nobody seemed to understand how I felt. My husband and son were marvellous, but they were having to stay off work and lose their money, but it’s so wonderful to begin to feel safe again.’ So really, she’s talked about physical pain, she’s talked about emotional pain of feeling shut away and all the emotional burden that she couldn’t share. She was talking about social pain, financial in that case, but the impact on her family. And then the spiritual need, I think it is spiritual, of the security, the safety, to look at herself and who she was and just be herself. And then the concept of what I called total pain, and really started to lecture about, really comes from there.

Cicely Saunders

This chapter will focus on the management of physical pain caused by cancer, but the principles of therapy are generally applicable to the management of pain caused by other progressive, non-malignant conditions.

Pain is a common and feared symptom of cancer (Table 6a.1). Many patients with non-malignant, life-threatening disease also suffer pain. Despite the availability of effective methods of controlling pain, significant numbers continue to receive inadequate pain relief.

Cancer pain may be acute or chronic, and chronic pain may be further subdivided:

What we were aiming at as we started to work together in St Joseph’s, was a patient who was alert and themselves and free of pain. For the great majority of patients that isn’t that difficult with drugs that are available to anybody in a method that is simple. But it does include the very important careful analysis and assessment at the beginning. One long interview and careful examination can carry an awful lot of shorter ones.

Cicely Saunders

Failure to assess pain is a critical barrier to good pain management.

I think there’s a pain somewhere in the room, but I could not positively say that I have got it.

Mrs Gradgrind (Hard Times, Charles Dickens)

Failure to assess pain is the most common cause of poor pain control. Pain scales can be useful tools in the systematic assessment of symptoms. Not only can they can encourage patient communication and facilitate the professional’s understanding of the patient’s experience, they can also be used to chart the trend of the patient’s response to therapy. However, tools should never be seen as substitutes for a complete pain assessment. Moreover, they may need to be tailored to the needs of specific populations, for example generic tools are often unsuitable for use with those people who are cognitively impaired.

The ideal qualities of a pain assessment tool are that:

Pain assessment tools may be unidimensional or multidimensional:

The VAS is a line with extremes marked as ‘no pain’ and ‘worst pain’. Patients are asked to mark the point in the line that best describes their pain.

No pain_________________________Worst pain

These involve a sequence of words describing different levels of pain intensity e.g.:

None Mild Moderate Severe

These use numbers or gradations that indicate the severity of the pain experience:

0___1___2___3___4___5___6___7___8___9___10

No pain                Worst pain

Pain is under-reported and under-treated in cognitively impaired older people. A comprehensive review of the literature reveals that people dying with dementia represent the ‘disadvantaged dying’.⁴

As dementia progresses, and cognitive function and the ability to communicate verbally declines, it becomes increasingly more difficult to ascertain accurately wishes and needs and, consequently, people with dementia often have painful conditions that go unnoticed. This loss of language communication presents a major challenge in assessing pain in this group as self-reporting is required for most pain assessment tools.

In the absence of verbal self-report, nurses and carers are forced to rely increasingly on non-verbal and behavioural cues of physical and emotional pain. They need to use a combination of indicators to determine levels of pain, e.g. crying, facial grimacing, etc. Using observation skills rather than relying on verbal responses is essential, as is consideration that any sign of agitated behaviour may be emotional and not a result of pain.

Behaviour commonly associated with pain may be absent or difficult to interpret; e.g. extrapyramidal signs in people with dementia syndromes may mislead the healthcare professional, who may interpret the movements as an indication of pain.⁵ There is no agreed physiological or biological chemical marker of pain and in people who are unable to communicate there is no benchmark that can be used to allow a definitive diagnosis of pain.⁵

A number of pain assessment tools have been developed for use in people with dementia.^6,7 However, it remains a complex area of clinical assessment practice. It is important to select a scale that matches the person’s abilities; even their pre-dementia educational level and pre-existing abilities influence their ability to use pain scales.^5,6

Enlisting the assistance of a carer or family member who is familiar with the usual behaviours and responses of the person with dementia is also essential in identifying behaviour changes that may indicate pain or discomfort.

The Abbey Pain Scale is an assessment tool that is presented in a form suitable for clinical use and is both easy and quick to administer. It was developed with care-home residents with end- or late-stage dementia using a combination of quantitative and qualitative data collection and analysis processes.⁸

The Abbey Pain Scale has been shown to be most useful as an aid to intervention where the scale is used to assess changes prior to, and following the administration of analgesia (Fig. 6a.2).

Many of the principles of assessing and managing pain in people with dementia also apply to people with learning disabilities when providing end-of-life care. The Disability Distress Assessment Tool (DisDAT),^9,10 developed to aid in the assessment of distress in people with learning disabilities, may also be of use in guiding practitioners in assessing distress in the dementia group.

Two main types of pain may be identified on the basis of the mechanism by which pain is produced: nociceptive and neuropathic. Different types of pain respond with varying degrees of effectiveness to different types of analgesics, and so it is important that clinicians determine what type of pain a patient is experiencing in order to prescribe the most appropriate drug. Many patients with cancer have mixed pain syndromes, i.e. a combination of nociceptive and neuropathic pain, and may need combination therapy.

Nociceptive pain may result from injury to somatic structures (somatic pain) or injury to visceral structures (visceral pain) (Fig. 6a.3.):

Neuropathic pain is caused by injury to the peripheral and/or CNS (Fig. 6a.4). The underlying mechanisms of neuropathic pain are poorly understood, but broadly speaking, pain occurs because the injured nerves either react abnormally to stimuli or discharge spontaneously.

More than twenty years ago, the World Health Organization (WHO) published Cancer Pain Relief,¹² a book which set out the principles of cancer pain management including the use of the three-step analgesic ladder. The WHO method can be summarized in five phrases:

The WHO ladder indicates that a structured, yet flexible, approach to the management of cancer pain is important. The steps of the ladder illustrate that the process of selecting analgesics should be dependent on an assessment of the intensity of pain experienced by the patient, rather than aetiology of the pain.

The oral route is the preferred route for analgesics, including morphine. For persistent pain, analgesics should be taken at regular time intervals and not ‘as needed’. Adjuvant drugs should be prescribed when required.

Each patient should be regularly re-assessed in order to determine response to treatment, and to ensure that he/she experiences maximum benefit with as few adverse effects as possible. Pain relief can be achieved for about 80% of patients by adopting the basic principles of ‘by the mouth, by the ladder and by the clock’.¹³

The three classes of analgesics referred to in the WHO analgesic ladder are: non-opioids, opioids and adjuvants (co-analgesics) (Fig. 6a.5).

Non-opioids are analgesic drugs that mediate their effect through receptors other than opioid receptors. Examples of non-opioids are aspirin, paracetamol and NSAIDs.

Opioids are drugs that are agonists at opioid receptor sites. There are at least three types of opioid receptor (mu, kappa and delta), which are found in several areas of the brain and throughout the spinal cord. Stimulation of opioid receptors results in a variety of responses, including analgesia, respiratory depression, myosis, reduced gastrointestinal motility and euphoria. Differences between opioids relate, in part, to differences in receptor affinity.

Opioids for mild to moderate pain are so-called because they are conventionally used to treat pain of this intensity. They are sometimes called referred to as ‘weak’ opioids.

Opioids for moderate to severe pain are used to treat moderate to severe pain and are sometimes called ‘strong opioids’. They are available as immediate release and modified release preparations. Immediate–release (i/r) opioids typically reach peak plasma concentrations within one hour of ingestion and have a duration of action of 1–4h, depending on formulation. Modified-release (m/r) opioids typically reach their peak plasma concentrations 2–6h after ingestion, and the plasma levels are sustained over a period of 12–24h, depending on formulation.

These are drugs which do not function primarily as analgesics but can act to relieve pain in specific circumstances. The choice of adjuvant drug is generally guided by the nature of the underlying pain (i.e. nociceptive or neuropathic). Examples of adjuvant analgesics are listed in Table 6a.3.

Breakthrough pain is a transient increase in pain intensity over background pain. Usually, breakthrough pain is related to background pain; typically, it is of rapid onset, severe in intensity and self-limiting, with an average duration of 30 minutes.¹⁵

Three types of breakthrough pain are described:

Breakthrough pain affects over 50% of patients with cancer, and also occurs in patients with non-malignant disease. It is a poor prognostic indicator¹⁷ and may lead to decreased functioning, anxiety and depression and longer stays in hospital.^18,19 Every patient on an opioid should have access to breakthrough analgesia in order to ensure optimal pain control.

Pharmacological management should be tailored to the type of breakthrough pain:

Patients with mild pain should be treated with a non-opioid analgesic, and if a specific indication exists, the use of the non-opioid analgesic may be combined with that of an adjuvant analgesic.

For example, a patient with mild neuropathic pain may be prescribed paracetamol 500mg–1g q6–8h regularly (max. daily dose 4g) in combination with amitriptyline 25–75mg o.d.

Patients who fail to achieve adequate relief after a trial of a non-opioid analgesic, or who present with moderate pain, should be treated with an opioid conventionally used for the treatment of mild to moderate pain. The opioid may be combined with a non-opioid in order to achieve an additive analgesic effect. Adjuvant drugs may also be used as required.

For example, a patient with moderate neuropathic pain may be prescribed codeine 30–60mg q6h in combination with paracetamol 1g q6h and amitriptyline 25–75mg o.d.

Some authors have questioned the usefulness of step 2 of the ladder because, in a systematic review, opioids for mild to moderate pain (either alone or in combination with non-opioids) were shown to be no better than full doses of NSAIDs alone.²¹ In practice, however, clinicians have found the range of choices afforded by the ladder to be helpful.

Combination preparations of opioids and non-opioids are available for use at step 2, and are some of the most widely used medicines in the community. e.g. co-codamol

Patients who fail to achieve adequate relief despite appropriate prescription of step 2 drugs, or who present with severe pain should be treated with an opioid conventionally used for severe pain. Adjuvant drugs may be used as required.

Oral morphine, in either immediate-release (i/r) or modified-release (m/r) form, is the opioid of choice for treating moderate or severe cancer pain for reasons of its familiarity, availability and cost.

Aspirin, paracetamol and NSAIDs are all possible step 1 analgesics, although in practice aspirin is difficult to tolerate at analgesic doses due to its side-effects. The choice between paracetamol and the NSAIDs should be based on a risk/benefit analysis for each patient.

Paracetamol’s analgesic and antipyretic activities are similar to that of aspirin, but it lacks an anti-inflammatory effect. Its mode of action for its analgesic effect remains unclear, although serotonin modulation has been suggested. It has minimal toxicity in adults at recommended doses, but at higher doses can cause fatal hepatotoxicity and renal damage.

NSAIDs are a heterogenous group of drugs that are of use in the treatment of pain mediated by prostaglandins, which serve to sensitize nociceptors. They have conventionally been thought to have particular use in the management of bone pain, but their analgesic effect in this area has probably been somewhat over-estimated.

NSAIDs produce their analgesic effect through inhibition of one or both of the isoenzymes of cyclo-oxygenase: COX-1 or COX-2.

Non-specific COX inhibitors, such as aspirin, ibuprofen and diclofenac, inhibit both isoenzymes. But their use is associated with a number of adverse effects (notably GI and renal toxicity).

Newer NSAIDs inhibit COX-2 only, and are associated with reduced GI effects. However, they may still adversely affect renal function and they have recently been associated with an increased risk of adverse vascular events. Several epidemiological studies have implied that the increased risk of vascular events is a class effect, and is associated with the use of conventional NSAIDs also; this area is being closely studied

Tables 6a.4 and 6a.5 provide guides to NSAID selection and dosages, respectively, in palliative care practice.

Codeine is metabolized by the hepatic cytochrome enzyme CYP2D6 to morphine. Codeine is a much weaker agonist at mu receptors than morphine, and the analgesic effect is highly dependent on the production of its active metabolite, morphine, by the CYP2D6 system.

Some 7% of Caucasians and 1–3% of Asian people are CYP2D6 poor metabolizers, and do not experience effective analgesia with codeine. CYP2D6 activity may also be inhibited by antipsychotic agents (haloperidol, levomepromazine and thioridazine) and antidepressants (amitriptyline, fluoxetine and paroxetine).

Codeine is available in tablet and syrup formulations. Doses of 30–60mg p.o. q4h are generally prescribed, to a maximum dose of 240mg in 24 hours. It is also available in compound preparations, where it is combined with a non-opioid. The compound preparations may contain either low-dose (8mg) or high-dose (30mg) codeine, and so it is important to stipulate the dose of codeine required in the preparation, e.g. ‘paracetamol 500mg/codeine 30mg’. Studies have shown that there is no additional analgesic benefit from preparations that contain only 8mg of codeine combined with paracetamol compared with paracetamol alone.

Tramadol displays weak opioid activity and it is also a noradrenaline and selective serotonin-reuptake inhibitor (SSRI). It is metabolized by both CYP2D6 to the active metabolite, and additionally by CYP3A4. Like codeine, CYP2D6 inhibitors can reduce its analgesic effect. CYP3A4 inducers (e.g. carbamazepine) can also reduce analgesia.

There is some disagreement as to which step of the ladder tramadol should be prescribed. But, traditionally, it has proved suitable as a step 2 analgesic because, at therapeutic doses, its analgesic effect is similar to that of an opioid for mild to moderate pain in combination with a non-opioid.

It is not classed as a ‘controlled drug’ and this has some practical prescribing advantages. One of the limitations of tramadol in cancer pain is the extent to which the dose can be titrated. It is recommended that, except in special clinical circumstances, doses of 400mg a day should not be exceeded. At doses above this, the risk of convulsions may be increased.

Opioids are safe, effective and appropriate drugs for the management of cancer pain, provided that:

Morphine is the strong analgesic of choice unless there is a clinical reason to use an alternative opioid ( p.245).

Morphine metabolism can be induced or inhibited by a variety of medications:

The starting dose of morphine depends on whether or not the patient has used opioids before and his/her previous dose.

An i/r morphine regime gives greatest flexibility for initial dose titration, but it may be appropriate to start some patients directly on m/r morphine, e.g.:

The management of opioid-related adverse effects is a fundamental aspect of opioid therapy, and clinicians should adopt a proactive approach, wherever possible. The use of opioid analgesia should not be affected by unfounded fears about pharmacological tolerance, dependence or respiratory depression. In the palliative care setting, pharmacological tolerance and psychological dependence rarely occur. There is often significant inter-individual variation in sensitivity to opioid-related adverse effects, and this may be explained, in part, by genetic variability. Other factors influencing the development of adverse effects are:

Many of the side-effects caused by opioids are non-specific, so it is important as a first step to determine whether the symptoms are related to opioid use or to underlying disease.

Common management strategies for various opioid-related side-effects are listed in Table 6a.6, and are mainly based on a dose reduction of systemic opioid ± use of a specific therapy to treat the adverse effect.

Additional strategies for the management of opioid-related side-effects include:

Opioid toxicity may be precipitated by:

In the palliative care setting the IM route is normally avoided because of issues of painful injections, cachexia and reduced muscle mass. The SC route is often used, and is appropriate for those patients who are unwilling or unable to take oral medications for such reasons as:

SC administration is not an alternative to ineffective oral treatment. In such cases, the clinician should reassess the patient, determine the reason for their poor response to therapy, and develop a targeted plan to deal with the problem.

Opioids have different analgesic potencies when administered by different routes. Doses of opioids need to be adjusted, therefore, when their route of administration is altered in order to avoid under- or over-dosing. For example, intrathecal and epidural morphine are approximately 100 and 10 times, respectively, more potent than oral morphine.

A number of alternative strong opioid analgesics are available which have their place in palliative care practice (Table 6a.7):

The decision to use alternative opioids in place of morphine is best made by a palliative care specialist. Rigorous evidence favouring the use of one opioid over another is often lacking, but it is generally accepted that individual opioids have characteristics that may result in clinicians preferentially using a particular opioid in certain clinical situations (Table 6a.8).

A number of factors influence choice of an appropriate opioid:

The equianalgesic doses of different opioids drugs are only approximations. A number of factors can affect their accuracy:

Diamorphine is more soluble in water than morphine, and is used as an injectable strong opioid in a syringe driver for subcutaneous infusion.

NB It is unusual to give diamorphine IV in a hospice setting. Subcutaneous administration is most commonly used (onset of action is 10–20 minutes) unless the pain is very severe and immediate relief is needed.

To convert from oral morphine to SC diamorphine, divide the total dose of oral morphine by three, e.g.:

The switch to methadone is successful (i.e. improved pain relief and/or reduced toxicity) in about 75% of patients.

If switching from immediate release morphine (e.g. oramorph):

If switching from modified release morphine:

Example 1: Morphine 300mg/24h p.o. = loading dose of methadone 30mg p.o., with 10mg 3hourly p.r.n.

Example 2: Morphine 1200mg/24h p.o. = loading dose of methadone 120mg p.o., with 40mg 3hourly p.r.n.; however, both are limited to the maximum of 30mg.

Example: Methadone 80mg p.o. in previous 48h=Methadone 20mg every 12h and 5mg p.o. every 3h p.r.n.

If ≥2 doses/day of p.r.n. methadone continue to be needed, the dose of regular methadone should be increased once a week, guided by p.r.n. use.

Converting oral opioid (other than morphine) to oral methadone

Converting from oral methadone to SC methadone

For patients in severe pain and who need more analgesia in < 3h:

Although SC methadone has been used, there may be problems with skin reactions, partly because methadone in solution is acidic. If it is necessary to use SC methadone, dilute it as much as possible.

Direct CSCI switching between other opioids and methadone is not recommended.

Although opioid receptors are not evident in normal tissue, they are found in inflamed tissue. As a result, there has been some interest in the efficacy of topical opioids for the management of ulcers and pressure sores. The use of topical opioids is associated with the potential advantage of a reduction or avoidance of the adverse effect profile associated with the use of systemic opioids.

Most studies describing the topical effects of morphine have mixed the opioid in Intrasite gel, although there are anecdotal reports, in which morphine (or diamorphine) has been mixed with flamazine or metronidazole gel.

A randomized, double-blind, placebo-controlled, crossover pilot study reported an analgesic effect when morphine was applied topically to painful ulcers.³⁸ However, patient numbers were small and, therefore, the data should be interpreted with caution. Treatment was generally well tolerated by patients, and although local reactions were described during the study, these were mild and possibly not related to morphine. No systemic adverse effects were reported.

The following tables show the approximately equivalent oral, transdermal and subcutaneous opioid doses.

Transdermal patches are not suitable for patients who require rapid titration of strong opioid medication for severe pain and should be restricted to those diagnosed with stable pain.

Caution should be used when converting opioids in opposite directions as potency ratios may be different

Pain is a more terrible lord of mankind than even death itself.

Albert Schweitzer (1875–1965)

Various protocols have been described:

Patients who have chronic unremitting pain from a deteriorating condition are particularly at risk of spiritual pain. Referral for psychological/spiritual support is important, and/or that of a complementary therapist.

Using Hay’s seven-model assessment,³⁹ (spiritual pain) is broken down into:

The medical treatment of neuropathic pain is unsatisfactory, and pain can prove difficult to control in a significant number of patients with this condition.

The early trials of analgesics for neuropathic pain considered neuropathic pain as a uniform entity, but more recent trials have assessed various pain syndromes. It has emerged from this data that analgesics may vary in efficacy according to the type of pain syndrome. Most of the trials on neuropathic pain have studied patients who have post-herpetic neuralgia and painful polyneuropathy. Fewer trials have looked at neuropathic pain due to cancer infiltration, and, as a result, much of the data on the efficacy of different drugs is extrapolated from data collected from patients with non-malignant pain.

The NNT (number of patients needed to treat to obtain one responder to the active drug) is commonly used as an indication of the overall efficacy of individual drugs. It is a relatively crude measure however, as it can be hampered by methodological variability across RCTs and a lack of consideration for other important outcomes (e.g. quality of life).

Table 6a.13 lists the NNT of analgesics on the basis of data listed in the European Federation of Neurological Societies (EFNS) guidelines. The data was taken from class I/II studies on painful polyneuropathy with 95% confidence intervals (CI). Unless otherwise specified, the NNT used was for 50% pain relief.

The mechanism of action of antidepressant drugs in the management of neuropathic pain is unclear. Analgesia is often achieved at a lower dosage and faster (usually within a few days) than the onset of any antidepressant effect (which can take up to six weeks). The pain-relieving properties of antidepressants are independent of any effect on mood.

Two main groups of antidepressants are commonly used:

TCAs are often listed as first-line drugs for the treatment of neuropathic pain. In terms of NNT, they appear to have a similar efficacy regardless of the underlying condition: diabetes mellitus, post-herpetic neuralgia,traumatic nerve injury or stroke.