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Treatment for moderate pain

Written by | 30 Jan 2013 | All Medical News

This article has been initiated, funded and reviewed by Mercury Pharma.  The management of moderate pain can be a challenge as it calls for more than simple analgesics but less than strong opioids. Finding the right combination of weak opioid and simple analgesic can be difficult. The launch/availability of Codipar capsules (link to PI) in Ireland, a fixed combination of codeine 15mg and paracetamol 500mg, provides a useful middle step that can help prescribers to titrate doses to achieve effective pain relief with minimal side effects.1

The WHO analgesic ladder, first introduced in 1986 for the management of cancer pain, still serves as a framework for the prescribing of analgesics. (See figure 1) Step 1 of the ladder (mild pain) calls for simple analgesics with or without adjuvants. Step 2 involves the use of weak opioids (e.g. codeine, dihydrocodeine tramadol) with or without simple analgesics and adjuvants. Step 3 involves the use of strong opioids e.g. morphine, with or without simple analgesics and adjuvants.2

WHO Ladder


From: http://www.who.int/cancer/palliative/painladder/en/index.html


The efficacy of the WHO analgesic ladder is reliant upon 5 simple recommendations for the correct use of analgesics being adhered to:

1.   Oral administration of analgesics. The oral route for delivery of analgesics is preferable whenever possible. Obviously, in acute pain situations this is not always applicable; however, it is advised that once patients are able to tolerate oral medication that the route of administration is changed to this.

2.   Analgesics should be given at regular intervals. To relieve pain adequately, it is imperative that the efficacious duration of the analgesic is taken into account and to prescribe the dosage to be taken at definite intervals in accordance with the patient’s level of pain.

3.   Analgesics should be prescribed according to pain intensity as evaluated by a scale of intensity of pain. As previously described in the pain assessment module analgesia should only be prescribed after a comprehensive assessment of pain (including a clinical examination) has been performed. The WHO analgesic ladder explicitly recommends that the analgesia be prescribed according to the level of the patient’s pain utilising a valid pain tool.

4.   Dosing of pain medication should be adapted to the individual. There is no standardized dosage in the treatment of pain as every individual will respond in a different way. The correct dosage is one that will allow adequate relief of pain whilst causing minimal side effects.

5.   Analgesics should be prescribed with a constant concern for detail. The regularity of analgesic administration is crucial for the adequate treatment of pain. Analgesics should be given “by the clock”, that is every 3-6 hours, rather than “on demand.” This stepped approach of administering the right drug in the right dose at the right time is inexpensive and generally effective in managing acute pain.

One of the useful properties of the WHO analgesic ladder is that it can be used as a framework for the management of both acute and chronic pain. For chronic pain doses are titrated upwards until control is achieved. For acute pain, treatment is often started at level 2 or 3 and titrated downwards.

The effectiveness of the ladder rests on the application of five simple but important principles: 2


  • Oral administration whenever possible
  • Analgesics should be given at regular intervals (‘by the clock’)
  • Analgesics should be prescribed according to the intensity of the pain
  • Dosing should be adapted to the individual
  • Analgesics should be prescribed with a constant concern for detail

Thus, the ladder is a framework and a starting point but achieving affective relief of pain for an individual still requires selection of the most appropriate analgesics and adjustment of the doses.

Step 2 of the analgesic ladder involves prescribing of a weak opioid, such as codeine or dihyrocodeine with or without a non-opioid – in practice this will be a simple analgesic such as paracetamol or aspirin or a NSAID such as ibuprofen.  The rationale for combining two different types of analgesics is to take advantage of the additive analgesic effects relief whilst minimising the risk side effects from high doses of either agent alone.3

Paracetamol (acetaminophen) is a simple analgesic that is well-tolerated and available without prescription. It has analgesic and antipyretic effects similar to those of aspirin. But has only weak anti-inflammatory effects.4 The maximum daily dose of paracetamol is 4G (4000mg, 8 x 500mg tablets). Paracetamol has been widely available for decades and has a good safety profile, provided that the daily dose does not exceed 4G (IN ADULTS). 5

Codeine is a weak opioid that owes its analgesic effect to its conversion to morphine.3 (ref G&G 566a) The maximum (oral) daily dose is 240mg. 6

Codeine can cause dose-dependent side effects similar to those of morphine i.e. dizziness, drowsiness, nausea, vomiting constipation. The conversion of codeine to morphine is brought about by CYP2D6 and due to well-characterised genetic polymorphisms of CYP2D6, about 10% of the Caucasian population is unable to perform this conversion, making codeine ineffective for them.3

Up until recently, two fixed combinations of codeine and paracetamol have been available in Ireland- a combination of 8mg codeine and 500mg paracetamol, as an over-the-counter (OTC) product and a combination of 30mg codeine with 500mg paracetamol as prescription-only product. More recently the combination of 15mg codeine with 500mg paracetamol has become available in Ireland. This is a prescription-only item and has the merit of ‘bridging the gap’ between the two longer-established fixed combination products.

There is good evidence detailing the effectiveness of paracetamol and codeine combinations. 7The combination has an important place in the therapeutic arsenal when effective analgesics are required for moderate pain, for example post-surgical pain.2

One study randomly compared the analgesic efficacy of paracetamol alone with three different codeine /paracetamol combinations (20mg +500mg, 30mg +500mg and 40mg +500mg) in patients who had undergone surgery to remove impacted lower wisdom teeth.4 (ref Quiding) The results showed that the best pain relief was obtained with the combination paracetamol 500mg + codeine 40mg (ref p316a)7. The duration of pain relief was also related to the dose of codeine. (ref p316b)7 This study also showed that the frequency of side effects such as dizziness and nausea increased as the dose of codeine increased, although none was serious. (ref p318)7

A subsequent systematic review of studies that compared paracetamol alone with paracetamol-codeine combinations confirmed that the combinations produced significantly better pain relief than paracetamol alone.1 (ref de Craen p324)  In the studies included in the review the doses ranged from 400 – 1000mg paracetamol and 10-60mg codeine. (ref 321) The results also showed that increasing amounts of codeine were associated with a higher frequency of side effects. (ref p323) This underlines the importance of having a combination that contains a dose of codeine that is sufficient to increase the level of analgesia without increasing risk of side effects.

Whether moving up or down the ladder the availability of the codeine 15mg-paracetamol 500mg combination provides the prescriber with a degree of flexibility to achieve effective analgesic effects with minimal side effects. Side effects that make it difficult to function normally are of concern to patients. In a recent survey of public attitudes to pain conducted in the UK 8, 45% of the surveyed population were particularly keen to avoid drowsiness caused by analgesics.

Finding the right combination of weak opioid and simple analgesic can be a challenge for the pain management team. The launch/availability of Codipar capsules, a fixed combination of codeine 15mg and paracetamol 500mg provides another useful tool that will create a middle step of analgesia and help prescribers to titrate doses to achieve effective pain relief with minimal side effects.1




1. Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: a systematic review. de Craen AJM, Di Giulio G, Lampe-Schoenmaeckers AJEM, Kessels AGH, KleijnenJ.  BMJ 1996;313:321-5

2. WHO analgesic ladder  http://www.who.int/cancer/palliative/painladder/en/index.html

3. Opioid analgesics. Chapter 2 in Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Eds Brunton LL, Lazo JS & Parker KL. 11th ed. McGraw-Hill 2006

4. Analgesic-antipyretic agents; Pharmacotherapy of Gout. Chapter 2 in Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Eds Brunton LL, Lazo JS & Parker KL. 11th ed. McGraw-Hill 2006

5. http://www.medicines.org.uk/emc/medicine/24178/SPC#POSOLOGY

6. http://www.medicines.org.uk/emc/medicine/23916/spc#POSOLOGY

7. Quiding H, Persson G, Ahlström U, Båmgens S, Hellem S, Johansson G, Jönsson E, and Nordh PG. Paracetamol Plus Supplementary Doses of Codeine: An Analgesic Study of Repeated Doses. Eur J Clin Parmacol 1982; 23:315-319

8. Public attitudes to pain. Public’s Perception of Pain. Report The Patients Association. November 2010

Job Bag No – IRE/COD/WEB/357/2012

December 2012

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