Professor Marie Fallon reviews the SIGN recommendations on using non-opioid and opioid formulations to control both background and breakthrough pain in patients with cancer

Pain associated with cancer increases with progression of the disease. Approximately one-third of patients with cancer report pain. However, the effectiveness of pain control in patients with cancer is variable.1

In 2008, SIGN published Control of pain in adults with cancer, which was not intended to serve as a standard of care, but rather as a guideline.1 This article builds on the SIGN guideline with interpretation of the generally low-level evidence for clinical practice.

World Health Organization analgesic ladder

The SIGN guideline is based on the principles outlined in the World Health Organization (WHO) cancer pain relief programme and it recommends that a patient’s treatment should be initiated at the step of the WHO analgesic ladder appropriate for the severity of the pain (see Figure 1).1,2 It is widely accepted from the quoted literature that around 85% of cancer-pain cases could be controlled by appropriate implementation of the WHO recommendations, underpinned by an accurate patient assessment and appropriate non-pharmacological approaches.3

Figure 1: Adaptation of the WHO analgesic ladder to show analgesic treatment options1,2

graph

*Non-opioids and adjuvants can be used at any step.
WHO=World Health Organization; NRS=numerical rating scales; NSAIDs=non-steroidal anti-inflammatory drugs

Step 1: non-opioid drugs

Non-opioid drugs may be used at any stage of the WHO analgesic ladder. Their use may result in synergistic effects when used with opioids, producing better pain relief at lower doses of opioids with potentially fewer opioid side-effects.1

Paracetamol and NSAIDs
The first step on the WHO analgesic ladder is designed to treat mild pain, and recommends the use of paracetamol and/or non-steroidal anti-inflammatory drugs (NSAIDs). 1,2

Both paracetamol and NSAIDs can be considered either alone (step 1) or in combination with opioids (step 2 and 3) to improve analgesia and reduce opioid-related side-effects. It is generally accepted that paracetamol is introduced first with an NSAID added to paracetamol or substituting paracetamol if indicated. Non-steroidal anti-inflammatory drugs are to be considered as second choice in mild pain.

Adjuvant drugs for neuropathic pain
Pain caused directly by cancer is probably mediated by a mixture of nociceptive and neuropathic mechanisms. The definition of neuropathic cancer pain is not standardised. The clinical impression of the clinician is key in the decision that a neuropathic element may be present.4 Observational studies have shown that neuropathic mechanisms are judged to be present in approximately 40% of patients with cancer pain,5 and in these individuals, additional drugs are often used alongside opioid analgesia.

Adjuvant drugs target specific mechanisms commonly involved in neuropathic pain and the most frequently used are tricyclic antidepressants, such as amitriptyline and imipramine, and anticonvulsants, such as gabapentin and pregabalin. The use of gabapentin or amitriptyline in combination with opioids is recommended in patients with cancer pain that is only partially responsive to opioid analgesia and has a neuropathic element.1 Amitriptyline can be a good choice for the patient who is unable to sleep. The use of these drugs is likely to cause significantly increased adverse events.

Ketamine is an N-methyl-D-aspartic acid antagonist, which has significant preclinical evidence and is currently the subject of a large randomised controlled trial in cancer pain. Prescription is currently limited to the specialist setting with shared-care protocols in some areas.1 SIGN was unable to make a recommendation on the use of ketamine as an adjuvant analgesic because of insufficient evidence.1 Evidence for the use of cannabinoids in cancer pain as an add-on treatment is evolving.6 The SIGN guideline does not recommend the use of these drugs.1

Step 2: opioids for mild to moderate pain

If the patient is opioid-naïve and experiences mild or moderate pain, the use of opioid drugs with low analgesic potency, such as codeine, is indicated.1 Low-potency opioids can be considered drugs that provide sufficient pain relief for moderate pain, but are limited by a pharmacological analgesic ceiling dose if pain is more severe. These drugs are most frequently prescribed as combination preparations (usually with paracetamol). Terminology has been confusing: codeine used to be referred to as a ‘weak’ opioid,1 but has subsequently been described as an ‘opioid for mild to moderate pain’. More recently the term ‘step 2 opioids’ (referring to their place in the WHO ladder) has become a recognised way of referring to these drugs because it is easy to understand.

The important issue at this stage is to prescribe a therapeutic dose of codeine and paracetamol, which would be 60/1000 mg, respectively, four times a day.1 Tramadol with paracetamol is an alternative option advocated in other countries but is not explicitly recommended by SIGN.

The use of low doses of drugs that are normally used at step 3 (severe pain) has been debated. This could include low-dose oxycodone, morphine, or transdermal fentanyl. This method has the potential advantage of a simple upwards dose titration if pain is not controlled but seems opioid responsive. This technique may be clinically appropriate for some patients and success depends on an appropriately low starting dose to avoid unwanted side-effects.

Step 3: opioids for moderate to severe pain

Strong opioids that are used in palliative care include:1

  • morphine
  • alfentanil
  • buprenorphine
  • diamorphine
  • fentanyl
  • hydromorphone
  • methadone
  • oxycodone.

Immediate-release oral morphine administered every 4 hours is effective and safe and was the first rational pharmacological approach proposed to treat cancer pain.7 The improved availability of different opioids has resulted in greater experience with the use of these drugs. Oxycodone and hydromorphone are alternatives to oral morphine as an opioid of first choice.

No evidence exists demonstrating the superiority of one oral opioid over another; oral morphine, hydromorphone, and oxycodone preparations are to be considered equivalent as first-choice drug for moderate to severe cancer pain; however, SIGN has taken the conservative approach of recommending oral morphine as the first-line oral opioid and diamorphine as first-line parenteral opioid of choice.1 There is significant inter- and intra-individual variation in opioid response.8 This will be discussed further in opioid switching (see below).

Transdermal opioids
Fentanyl and buprenorphine are opioids with short-acting analgesic activity after intravenous or subcutaneous administration. Their low molecular weight, high potency, and lipid solubility make them suitable for delivery via the transdermal therapeutic system. Transdermal fentanyl and buprenorphine are administered increasingly for moderate to severe cancer pain because of their formulation and favourable pharmacological profile. The delivery system results in a slow build up of drug in plasma levels, but once reached these will remain clinically stable.9

Transdermal delivery of drugs can be useful in patients with oral or other gastrointestinal problems.9 This form of fentanyl and buprenorphine can be used in patients with stable oral opioid requirements as an alternative to oral slow-release opioids.1

Methadone
Methadone has often been considered an alternative to oral morphine but its pharmacokinetic characteristics of a very long and unpredictable individual half-life6 have meant that in clinical practice its use is usually initiated and supervised by a specialist.1 In this situation it is usually prescribed for the patient who has evidence of some elements of an opioid-responsive pain but that requires doses at a level associated with unwanted side-effects.

Breakthrough pain

The term ‘breakthrough pain’ has been used to describe a phenomenon whereby pain intensity suddenly increases to a moderate to severe level beyond controlled background pain.10,11 Implicit in this definition is the administration of regular opioid analgesia for background pain.12,13 The fundamental problem with standard immediate-release opioid medications is that the onset of action lags significantly behind the peak of the pain and the duration of analgesia is much longer than the breakthrough pain episode. This translates into poor pain control, with excessive drowsiness.

A variety of fast-acting fentanyl preparations are now available. These formulations have a more favourable pharmacokinetic profile for breakthrough pain than oral immediate-release morphine. The pharmacokinetic profile of these fentanyl preparations is closer to the characteristics of a typical breakthrough cancer pain episode.12

There is no simple relationship between the effective dose of oral and nasal transmucosal fentanyl and the regularly scheduled around-the-clock opioid. An initial dose titration protocol should be followed for safety reasons. The titration regimen may be different in the specialist setting. The SIGN guideline recommends that when using oral morphine for breakthrough pain the dose should be one sixth of the around-the-clock morphine dose and should be increased appropriately whenever the around-the-clock dose is increased.1

A number of alternative and arguably easier-to-use fast-acting, fentanyl preparations have become available since publication of the SIGN guideline. Transmucosal, oral, buccal, sublingual, and nasal fentanyl preparations should be considered in preference to immediate-release oral morphine in the treatment of breakthrough pain of a fast or unpredictable onset that has a relatively short duration. However, immediate-release oral morphine has a role in treating breakthrough pain in episodes that can be treated pre-emptively by at least 30 minutes.

Opioid titration

The traditional use of administering immediate-release oral morphine every 4 hours was not founded on controlled clinical trials but on longstanding clinical practice combined with pharmacological rationale based on the short half-life (2.7 hours +/-1.2) of oral morphine.13 The advent of slow-release oral morphine, oxycodone, and hydromorphone preparations has made it possible to maintain appropriate plasma levels to deliver analgesia for periods of time ranging from 12–24 hours,1 and with transdermal delivery systems of fentanyl and buprenorphine, for up to 3 days.9

This development encouraged the clinical practice of using slow-release oral opioid preparations or transdermal opioid delivery systems in opioid-naïve patients or those individuals previously exposed only to drugs at step 2. The literature has not identified any problems with this approach as long as appropriate starting doses are chosen. SIGN, however, favours the ‘conventional practice’ of starting with immediate-release morphine.

Titration can be performed with slow-release opioid formulations according to their pharmacological profile in combination with oral immediate-release opioids. The use of the immediate-release opioid (for breakthrough pain)—prescribed at one-sixth of the total 24-hour opioid dose—will guide dose adjustment of the slow-release preparation.

Opioid switching

Switching is the term given to the clinical practice of substituting one strong opioid with another when a satisfactory balance between pain relief and adverse effects is not achieved with appropriate titration of the first opioid, and this is recommended by SIGN; however this should always be accompanied by a reassessment of the patient and new drug therapy, and in particular adjuvant analgesic therapy.1 This practice is used relatively often by palliative care and pain specialists.

The favourable result of the new opioid can be seen as a shift in the therapeutic window at doses that are more effective while causing fewer side-effects. This can be partially explained by the concept of incomplete cross-tolerance.14,15 While no trial data of high quality exist to support this practice, the success rate of switching in observational studies is approximately 79% of cases.1

Opioid conversion ratio
The practice of switching from one opioid to another means that the dose of the new drug has to be both safe and potentially efficacious to achieve pain relief without undue adverse effects. These dose calculations have to take into account not only the now dated equipotency studies,15 but also the empirical evidence demonstrated by switching patients from one drug to another one in appropriate clinical situations.

The most important aspect to remember is that if a patient requires an opioid switch, it is important to make a conservative conversion as the patient will almost certainly be less tolerant to the new opioid. In particular if the switch is made to manage unwanted adverse effects, the new opioid dose has to be conservative (see Table 1) and the lower ratio derived from equianalgesic data should be used for safety. Regular assessment and reassessment of efficacy and side-effects is essential during conversion from one opioid to another.1

In clinical practice the commonest switch is a route switch (e.g. oral morphine to subcutaneous morphine or diamorphine. [diamorphine is simply diacetyl morphine and is metabolised to morphine]). Calculated ratios are more accurate for equianalgesic doses when referring to patients with good pain control and stable opioid doses. Clinically of course, this is not a group of patients who are likely to need an opioid switch.

Table 1: Suggested dose conversion ratios in the direction specified1
(Converting from)
Current opioid
(Converting to)
New opioid and/or new route of administration
Divide 24 hour dose* of current opioid (column 1) by relevant figure below to calculate initial 24 hour dose of new opioid and/or new route (column 2)
Example
120 mg oral morphine in 24 hours
subcutaneous diamorphine Divide by 3
(120 mg/3 = 40 mg subcutaneous
diamorphine in 24 hours)
Oral-to-oral route conversions
oral codeine oral morphine Divide by 10
oral tramadol oral morphine Divide by 5
oral morphine oral oxycodone Divide by 2
oral morphine oral hydromorphone Divide by 7.5
Oral-to-transdermal route conversions
oral morphine transdermal fentanyl Refer to manufacturer’s information
oral morphine transdermal buprenorphine Seek specialist palliative care advice
Oral-to-transdermal route conversions
oral morphine subcutaneous morphine Divide by 2
oral morphine subcutaneous diamorphine Divide by 3
oral oxycodone subcutaneous morphine No change
oral oxycodone subcutaneous oxycodone Divide by 2
oral oxycodone subcutaneous diamorphine Divide by 1.5
oral hydromorphone subcutaneous hydromorphone Seek specialist palliative care advise
Other route conversions rarely used in palliative medicine
subcutaneous or intramuscular morphine intravenous morphine No change
intravenous morphine oral morphine Multiply by 2
oral morphine intramuscular morphine Divide by 2

* The same units must be used for both opioids or routes (e.g. mg morphine to mg oxycodone)
†The conversion ratios of oral morphine:transdermal fentanyl specified by the manufacturer(s) vary from around 100:1 to 150:1
Scottish Intercollegiate Guidelines Network. Control of pain in adults with cancer. SIGN 106. Edinburgh: SIGN, 2008. Reproduced with kind permission of the Scottish Intercollegiate Guidelines Network


Alternative methods of administering opioids

Parenteral
The choice of parenteral opioid administration is often made necessary for patients who cannot swallow. Subcutaneous morphine, diamorphine, hydromorphone, oxycodone, and alfentanil infusions have been used as a first-line approach to maintain analgesia, and to treat other symptoms, in particular in the advanced or terminal phase of the disease.1,16,17

Epidural or intrathecal
Although not covered in the SIGN guideline, spinal opioid administration may be indicated in patients with excessive side-effects and insufficient pain relief from systemic opioids and appropriate adjuvant analgesics.18 This method has been used for many years in the management of cancer pain as it delivers much smaller doses of opioids close to the central nervous system (CNS), with improved analgesia and fewer adverse effects.

In addition, the possibility of adding local anaesthetic and/or clonidine is particularly useful in the common pains that require spinal analgesia, such as neuropathic and/or movement-related pain. The spinal infusion can be external or implanted. The former is more common and can be managed successfully in the patient’s own home with a small external infusion device. The management of spinal infusions in the community should always be overseen and appropriately supported by the specialist team.

Adverse effects of opioids

The majority of step 2 and step 3 opioids have four common side-effects: dry mouth, constipation, nausea, and drowsiness. Tolerance usually develops to the latter two effects but not to constipation and dry mouth.

Opioid-induced nausea and vomiting can be treated by using anti-emetic medications with an anti-dopaminergic effect1 or by changing the opioid or opioid administration route; first principles suggest either metoclopramide or haloperidol. Patients with established nausea and/or vomiting will need a parenteral route of administration to break the cycle.19

Constipation is the most predictable side-effect from chronic opioid administration. More specifically the problem is described as an ‘opioid-induced bowel syndrome’. Most patients on chronic opioid therapy require a regular laxative. Laxatives are recommended to manage opioid-related constipation,1 but there is no evidence of superiority of one type over another; however newer laxatives are often favoured.

Since the development of the SIGN guideline, newer approaches, such as slow-release naloxone combined with slow-release oxycodone or methylnaltrexone by subcutaneous injection can be used for prevention and treatment of constipation that is laxative resistant.

Opioid-related CNS symptoms
Opioid-related CNS side-effects may be underdiagnosed. Management strategies are limited and effort should be concentrated on prevention. It is important to monitor patients regularly for vivid dreams, shadows at the periphery of the visual fields, hallucinations, impaired cognition, and even frank confusion.1 Myoclonus can be present either alone or in combination with any of the aforementioned.20

Frank opioid toxicity carries a high mortality. In cases of patients with CNS symptoms, opioid dose should be reduced, biochemistry checked, and pain and all medication reassessed. Opioid toxicity should be treated by appropriate hydration, a reduction in opioid dose, a switch with a conservative conversion, and an appropriate dose of haloperidol (1.5–3.0 mg initially) to treat the frightening hallucinations, confusion, and/or agitation.8,20

Use of opioids in renal failure

The use of particular precautions in the administration of opioids in cancer patients with impaired renal function has been the subject of a number of guidelines, expert opinions, and interpretations.21 These preventative measures are based on known pharmacokinetics that cause the production and/or accumulation of active or inactive metabolites in patients with renal failure.1 It is only possible to base treatment recommendations on known pharmacology of available opioids as trial data do not exist.

Opioids should be used with caution in patients with significant renal function impairment, defined as glomerular filtration rate <30 ml/min.1 The safest opioids in renal dysfunction are alfentanil, buprenorphine, and fentanyl. All of the above drugs should be used at low starting doses and with very careful titration. Interestingly, buprenorphine (transdermal) is excreted almost unchanged in the faeces.1

Role of primary care

The primary care physician and the extended team are in the best position to understand the problems that cancer and cancer-related pain present for both the patient and family or carers. This insight is key to the assessment that underpins the correct clinical decisions for the patient.

Initial patient assessment and careful reassessment of wanted versus unwanted effects of any analgesia are vital to successful cancer pain control. We have in our armamentarium a large number of exceedingly effective analgesics and the secret to success is in the prudent assessment, prescription, and reassessment of the situation, rather than in an in-depth knowledge of intricate cancer pain mechanisms and complex pharmacology. Clearly the latter is of relevance in the more challenging situations in which palliative care specialists will be involved.

Discussion

Opioids are still the mainstay of any cancer pain management strategy. The key to success lies in patient assessment, careful opioid titration, attention to detail to prevent side-effects, and regular reassessment. Increasingly, the challenge is to find the optimum opioid drug and dose for the individual patient; however, there are currently no predictable ways of doing this.

Particular attention to opioid doses is required for patients near the end of life. At this time deteriorating renal function will result in an accumulation of opioid metabolites that can present through a variety of symptoms including agitation, confusion, and an apparent increase in pain. It is always important to consider opioid toxicity as a cause of escalating pain, and in such cases an increase in opioid will only serve to worsen pain.

The future will see an increase in the use of alternative opioids to morphine and with time we may even be able to predict which opioid would be best for a particular patient.

  • All primary care healthcare staff involved in cancer care should be aware of and actively use the WHO analgesic ladder
  • Commissioners should ensure they have established a local care pathway for cancer pain care as agreed by local specialists, and build this into local provider contracts
  • The pathway must be available to and used by all local healthcare providers including out-of-hours GP services
  • The pathway should link to and mandate the use of a local formulary—some preparations of analgesics are very expensive
  • Adequate control of cancer pain will help more patients experience end-of-life care at home and reduce inappropriate and expensive hospital admissions for terminal care
  • Tariff prices:a
    • phototherapy outpatient = £118 (JC29Z)
    • skin therapies outpatient = £138 (JC14Z).

awww.dh.gov.uk/paymentbyresults

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