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Stepped care for persistent pain

By Michael McDermott, MRPharmS


This series offers a simple, practical approach to continuing education.

Plan your learning using the “Objectives”, use the “Discussion points” to reflect on what you have read and “Test yourself” with the multiple-choice questions.

Why not try it with a group of colleagues at lunchtime?

Answers (bottom of page 2)
PDF (800K)

Chronic non-malignant pain is common, affecting one in seven people in the UK. Management should address the underlying cause of the pain and can involve the use of a range of analgesics


Chronic non-malignant pain (CNMP) can be described as any pain persisting beyond the time required for normal healing after injury or disease. It arises from non-life threatening causes and potentially persists for the remainder of a patient’s life.1

In the UK it is estimated that one in seven people are affected by CNMP, with an almost equal distribution between men and women (51% and 49%, respectively).2,3 The prevalence of CNMP increases with age.1

CNMP can be caused by medical conditions such as arthritis, peripheral neuropathy, intervertebral disc prolapse (slipped disc) or trauma. Like many other conditions CNMP has a negative effect on the quality of life of sufferers, impacting on social life, family, work and finances.

The management of CNMP should aim to treat the underlying cause, reduce disability and restore normal function.3 The approach should be holistic and involve a multidisciplinary team usually consisting of doctors, pharmacists, specialist nurses, clinical psychologists, physiotherapists and occupational therapists. The mainstay of treatment for CNMP is with analgesics. Pharmacists, therefore, are invaluable to patient care and should ensure that each patient’s medicines are optimised.

To treat pain effectively, it is important to remember that pain is an “unpleasant sensory and emotional experience”. The emotional element makes pain perception highly subjective and it is crucial for patients with CNMP to receive high-quality, personalised care.


The medicines used to treat CNMP will depend on the cause of the pain. If the pain is not neuropathic then the World Health Organization’s stepped approach can be used.4 If the pain is neuropathic (eg, peripheral neuropathy, postherpetic neuropathy, diabetic neuropathy or trigeminal neuralgia) then a different step-wise approach is followed.

Because of the chronic nature of the condition, patients with CNMP will often take analgesics long term. However, treatment should be reviewed at regular intervals and, if pain control is improved, consideration should be given to dose reduction or a step down in treatment.

WHO pain ladder

The WHO pain ladder, which was originally devised for the treatment of cancer pain, is a well established guideline for the management of patients with chronic pain — patients begin on step 1 and increase up to step 3 as necessary (see Figure 1).4

Patients who are not receiving sufficient analgesia at one particular step should be either “stepped up” to the next level of the ladder or their dose of current medicines should be increased. Adjuvant analgesics (such as baclofen) can be used at any step if indicated. Using this method, it is expected that around 80% of patients should receive adequate pain control.4

Step 1

Step 1 involves the use of non-opioid analgesics such as paracetamol or non-steroidal anti-inflammatory drugs. To improve outcomes at all stages of the WHO pain ladder, patients should be advised to take these medicines (particularly paracetamol) at regular intervals rather than on a “when required” basis.

Step 2

A weak opioid, such as codeine or dihydrocodeine, is used in combination with a non-opioid analgesic in step 2. In practice, this step of the ladder is often managed poorly, with some patients receiving combinations of weak opioids.

If a patient is not responding to maximum doses of one weak opioid then it is appropriate to move up to step 3 of the ladder. It is also useful to remember that prescribing a high dose of a weak opioid can result in an opioid load comparable to a low dose of a strong opioid (ie, 240mg of dihydrocodeine is roughly equivalent to 24mg of oral morphine).5

Weak opioids can have the same adverse effects as strong opioids, so patient counselling should be the same.

Step 3

Strong opioid analgesics such as morphine, fentanyl or oxycodone are required in step 3. Once a patient is stabilised on a dose of immediate-release opioid, he or she should be switched to the equivalent dose of a modified-release preparation if possible.

(This is to avoid pronounced peak and trough drug concentrations — reducing tolerance and drug misuse.)5

There is currently no high-quality evidence to suggest that one opioid is better than another. Also, the tolerability of different opioids will differ between patients.5 This effect is often down to differences in individual pharmacokinetics and pharmacogenomics.

Currently, there is a lack of data on the safety and efficacy of long-term opioid use. Therefore, it is important that the benefits of opioid analgesia are weighed judiciously against the potential adverse effects on a case-by-case basis.

In addition to the typical side effects of opioid therapy, long-term opioid use has been shown to impair the immune system and the endocrine system (eg, causing hypogonadism, reduced libido and infertility). These effects should be disclosed to the patient before starting treatment.5

Neuropathic pain

Patients with neuropathic pain respond poorly to conventional analgesics so using the WHO analgesic ladder is inappropriate for these patients. A protocol for the treatment of neuropathic pain6 can be
found online (PDF 800K).

Tricyclic antidepressants

The analgesic effects of tricyclic antidepressants (TCAs) are unrelated to their antidepressant activity — these are thought to be due to noradrenaline and serotonin elevating the pain threshold by modulating the nociceptive pathway in the dorsal horn, reducing pain transmission.7

In addition, TCAs have been shown to block sodium channels in sensory nerves.8 TCAs should be started at low doses and titrated to the minimum effective dose for each patient. Patients should be told that the analgesic effect is not produced immediately and in some patients can take up to eight weeks.9 It is important to note that TCAs are not licensed for the treatment of pain.

The National Institute for Health and Clinical Excellence currently recommends amitriptyline as one of the first-line options for the treatment of neuropathic pain.6

The main side effects include drowsiness, dry mouth, blurred vision, constipation and weight gain. If a patient finds the side effects unacceptable, switching to a secondary amine (eg, nortriptyline) can reduce adverse effects.

Higher doses of TCAs (>75mg a day) are associated with cardiac toxicity (particularly in patients with co-existing ischaemic heart disease) and arrhythmias. Therefore, these doses should be reserved for specialist use only.


Duloxetine is a selective noradrenaline and serotonin reuptake inhibitor and this activity is believed to account for its mode of action in both depression and analgesia (similar to TCAs). Current NICE guidance recommends that duloxetine should be used for the first-line treatment of diabetic neuropathy.6

Like TCAs, duloxetine should be started at a low dose and titrated up; NICE recommends a starting dose of 60mg daily but some patients (especially the elderly and those with renal impairment) may benefit from a lower starting dose of 30mg daily.

Generally, duloxetine is well tolerated — the most common side effect is nausea. It can take up to four weeks for patients to receive an analgesic effect.9


Pregabalin and gabapentin are both anticonvulsants  structurally related to the inhibitory neurotransmitter ?-aminobutyric acid. They act on sensory nerves by inhibiting neurotransmitter release through blocking calcium entry into the presynaptic nerve terminal. This blocks the transmission of pain signals to the brain. In addition to its analgesic effect, pregabalin also reduces anxiety.

Pregabalin can produce analgesic effects within four weeks of starting therapy, but gabapentin can take between five and 10 weeks (depending on patient tolerability and speed of titration).9

Both pregabalin and gabapentin can cause drowsiness, dizziness, peripheral oedema and gait disturbance.


Tramadol is a useful analgesic for patients with neuropathic pain that is uncontrolled using first- and second-line therapies. It binds to µ-opioid receptors, but it also inhibits the reuptake of serotonin and noradrenaline. The main side effects are drowsiness, dizziness, postural hypotension, nausea and constipation.9

Care must be taken when tramadol is co-administered with other serotonergic medicines (eg, duloxetine or TCAs) because of the risk of serotonin syndrome occurring. In addition, tramadol must be used with caution in patients with epilepsy since it can lower the seizure threshold.


Michael McDermott is a locum pharmacist and medical student. 




1    Wall PD, Melzack R. Textbook of Pain (4th ed). Philadelphia: Churchill Livingstone; 1999.

2    Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: Prevalence, impact on daily life and treatment. European Journal of Pain 2006;10:287–333.

3    The Royal College of Anaesthetists. Guidance on the provision of anaesthesia services for chronic pain management. 2009 (PDF 150K) (accessed 24 November 2010).

4    World Health Organization. WHO’s pain ladder (accessed 24 November 2010).

5    The British Pain Society. Opioids for persistent pain: Good practice (PDF 220K). London: The British Pain Society; 2010.

6    The National Institute for Health and Clinical Excellence. Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. March 2010 (accessed 24 November 2010).

7    Sindrup S, Otto M, Finnerup NB, et al. Antidepressants in the treatment of neuropathic pain. Basic and Clinical Pharmacology and Toxicology 2005;96:399–409.

8    Pancrazio JJ, Kamatachi GL, Roscoe AK, et al. Inhibition of neuronal sodium channels by antidepressant drugs. Journal of Pharmacology and Experimental Therapeutics 1998;284:208–14.

9    Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007;132:237–51.


Studying this article will help you gain a better understanding of:

  • The World Health Organization pain ladder
  • The management of neuropathic pain
  • The therapeutic profiles of drugs used for chronic non-malignant pain


Discussion points

What role do pharmacists have in the management of patients with chronic pain?

Should patients with chronic pain be offered long-term opioid therapy?


Test yourself

1    Which of the following are potential side effects of long-term opioid therapy?

a)    Reduced libido
b)    Hypogonadism
c)    Impaired immune function
d)    Infertility
e)    All of the above

2    Which of the following combinations is most likely to cause serotonin syndrome?

a)    Nortriptyline, duloxetine and tramadol
b)    Duloxetine, metformin and gliclazide
c)    Pregabalin, ramipril and aspirin
d)    Amitriptyline and pregabalin
e)    None of the above

3    On average, how long does it take for the analgesic action of duloxetine to take effect?

a)    Within 30 to 60 minutes
b)    Within five doses
c)    Within seven days
d)    Up to four weeks
e)    Between five and 10 weeks

4    Which of the following are side effects of pregabalin?

a)    Headache, flushing and tachycardia
b)    Sweating, polyuria and thirst
c)    Blurred vision, dry mouth and constipation
d)    Drowsiness, peripheral oedema and gait disturbance
e)    None of the above

5    Which of the following best describes the mechanism of action of tramadol?

a)    Opioid agonist
b)    Serotonin reuptake inhibitor
c)    Noradrenaline reuptake inhibitor
d)    All of the above
e)    Answers a and b

Answers (bottom of page 2) PDF (800K)

Citation: Clinical Pharmacist URI: 11067419

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