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Choosing over-the-counter analgesics

According to the Proprietary Association of Great Britain, 2007sales of analgesics reached £526m, making up 23 per cent of all OTCsales. There are numerous products available, but which can berecommended? Andrew Dickman reviews the situation in two articles. Thefirst, published here, focuses on the drugs. The second looks atcautions, contraindications and other considerations

by Andrew Dickman

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Identify knowledge gaps

1. Why is caffeine included in many over-the-counter painkillers?

2. Do naproxen and diclofenac have any benefits over the older OTC analgesics?

3. How effective are topical analgesics?

Before reading on, think about how this article may help you to do your job better.

The Royal Pharmaceutical Society’s areas of competence for pharmacists are listed in “Plan and record

This article relates to “common disease states” (see appendix 4 of “Plan and record”).

According to the Proprietary Association of Great Britain, 2007 sales of analgesics reached £526m, making up 23 per cent of all OTC sales. There are numerous products available, but which can be recommended?

Andrew Dickman reviews the situation in two articles. The first, published here, focuses on the drugs. The second looks at cautions, contraindications and other considerations

 

The International Association for the Study of Pain defines pain as “an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.

The fact that pain has an emotional component explains why it is always a subjective experience and patients with similar conditions will report different pain intensities.

A patient’s description of pain should be considered the most reliable indicator of suffering.

Pain is often classified by healthcare professionals using the terms “mild”, “moderate” and “severe” (sometimes assigned using a visual scale of 1 to 10).

On the whole, pains encountered in community pharmacies will be mild to moderate and self-limiting (less than one week), and will generally respond to any one of the wide range of over-the-counter analgesic products available.

Typical conditions presented include toothache, headache, dysmenorrhoea and musculoskeletal injuries. Moderate to severe pain will require strong opioids or adjuvant drugs.

Despite the large number of OTC products marketed for pain, most consist of one of only three active ingredients: aspirin, ibuprofen or paracetamol. According to a recent survey, one in four people are confused about the difference between common painkillers (YouGov survey of 2,112 UK adults, data on file).

Paracetamol

Paracetamol is the most widely used OTC analgesic and antipyretic. Its analgesic and antipyretic effects are similar to those of aspirin and ibuprofen but it is devoid of anti-inflammatory effects.

The mechanism of action of paracetamol is poorly understood, despite the drug having been available for over 50 years. It is generally accepted that the drug exerts its analgesic effect by inhibiting prostaglandin synthesis within the central nervous system but recent studies have suggested that serotonergic pathways are involved.

Paracetamol is a suitable choice for most patients requiring an analgesic for the management of mild to moderate pain. It is generally well tolerated and has no known gastrointestinal (GI), renal or cardiac adverse effects at usual doses.

Other adverse effects are rare. Hypersensitivity has been reported and typically presents as a skin rash. There have been rare cases of blood dyscrasias, including thrombocytopenia and agranulocytosis.

Paracetamol has only a few recognised drug interactions of any significance. It is largely metabolised by conjugation reactions in the liver, with a small proportion under-going oxidation by the cytochrome P450 isoenzymes CYP2E1 and CYP1A2. This latter pathway produces N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive compound. Ordinarily, NAPQI is conjugated with glutathione and excreted by the kidneys. Paracetamol hepatotoxicity can occur if glutathione reserves are depleted, enabling NAPQI to cause cell death. This mainly arises in situations of paracetamol overdose (>4g/day) but malnutrition can also result in decreased glutathione synthesis. Providing the maximum dose is not exceeded, paracetamol is a relatively safe and effective analgesic.

People also thought to be at risk of liver toxicity include those on long-term treatment with drugs that induce liver enzymes (eg, carbamazepine, phenytoin, St John’s wort). Smoking tobacco (nicotine) also induces liver enzymes. No specific recommendations on changing doses have been made but caution is advised.

Prolonged use of paracetamol can enhance the anticoagulant effect of coumarins.

Aspirin

Aspirin still popular despite having significantly worse safety profile than paracetamol (GustoImages/Science Photo Library)

Aspirin, the original OTC analgesic, is still popular despite having a significantly worse safety profile than paracetamol. It has analgesic, antipyretic, anti-inflammatory and antiplatelet properties. The analgesic effect of aspirin is mostly attributable to inhibition of cyclo-oxygenase (COX).

There are at least two isoenzymes, COX-1 and COX-2, which perform different functions (discussed in a previous CPD article; PJ, 9 June 2007, p679–82).

Inhibition of one or both of these isoenzymes reduces prostaglandin sensitisation of peripheral nociceptors. Aspirin can also have a central analgesic mechanism within the dorsal horn of the spinal cord.

The anti-inflammatory effect of aspirin is only seen at high doses (at least >3g daily) so, for this purpose, other NSAIDs are preferred because they are generally better tolerated.

The antiplatelet effect of aspirin occurs because it binds irreversibly to COX-1 in the platelet. This causes a reduction in the synthesis of thromboxane A2 and subsequent reduction in platelet aggregation. Although this presents beneficial cardiac outcomes, the risk of bleeding can be a major problem.

The adverse effects of aspirin are related to its nonspecific inhibition of COX-1 and COX-2. These include nausea and vomiting, epigastric pain, dyspepsia, gastrointestinal ulceration or haemorrhage (many patients can experience GI irritation with asymptomatic blood loss), hypersensitivity (eg, bronchospasm) and gout (uric acid secretion is inhibited).

Many of the adverse effects are dose- dependent, while others are idiosyncratic and unpredictable.

GI complications are more likely to occur in patients:

  • Aged 75 years or more
  • With hepatic or renal disease
  • Taking corticosteroids, other NSAIDs or selective serotonin reuptake inhibitors
  • Who have a chronic alcohol intake or who smoke

Aspirin has important interactions with anticoagulants, selective serotonin reuptake inhibitors and methotrexate.

Although it is widely accepted that aspirin is an effective analgesic, it can cause serious adverse effects and safer alternatives are available. Contraindications for aspirin will be discussed in the next CPD article.

Other NSAIDs

Ibuprofen became available OTC in 1984 but it was not until 2008 that two more NSAIDs were switched from prescription-only to pharmacy status. These were diclofenac (see Panel 1) and naproxen (see Panel 2), expanding the options for consumers. OTC naproxen is restricted to the treatment of dysmenorrhoea.

Panel 1: OTC diclofenac

Tablets containing 12.5mg diclofenac (Voltarol Pain-eze) can now be sold for the treatment of a variety of conditions, including the short-term management of headache, dental pain, dysmenorrhoea, musculoskeletal pain and the symptoms of colds and influenza.

It is licensed for use in adults and children over the age of 14 years and must not be used for longer than three days. The duration of action is estimated to be four to six hours, depending on the condition.1

Like ibuprofen, the anti-inflammatory effect of diclofenac is less marked at the OTC dose. The dosing schedule is straightforward. Initially the patient should take two tablets, followed by one or two tablets every four to six hours as needed.

No more than six tablets should be taken in 24 hours and the product must not be used for more than three consecutive days.

Panel 2: OTC naproxen

Naproxen 250mg tablets (Feminax Ultra) are available for the treatment of dysmenorrhoea. Prostaglandins that cause uterine muscle to contract, leading to the typical cramping sensation, are produced by the lining of the uterus during menstruation.

Naproxen inhibits the production of these prostaglandins and should, therefore, be an effective treatment. However, the OTC product may only be taken by women aged between 15 and 50 years old.

Due to the drug’s relatively long duration of action, patients can expect relief for at least six hours.2 The dosing schedule is simple. On day 1, the patient takes two tablets initially, followed by a further tablet six to eight hours later if needed.

If required, on day 2 and day 3, the patient can take one tablet every six to eight hours, to a maximum of three tablets in 24 hours. The patient must not take more than nine tablets in three days in any cycle

 

Like aspirin, these NSAIDs are non-specific COX inhibitors and have analgesic, antipyretic and anti-inflammatory properties. According to the British National Formulary, ibuprofen has fewer side effects than other NSAIDs but its anti-inflammatory properties are weaker.

It is, however, worth noting that the anti-inflammatory activity of ibuprofen is generally negligible at recommended OTC doses.3 Panel 3 compares maximum OTC doses with prescription doses.

Panel 3: Maximum daily adult doses of analgesics

 

OTC dose

Prescription dose

Aspirin3,900mg4,000mg
Diclofenac75mg150mg
Ibuprofen1,200mg2,400mg
Naproxen750mg1,250mg
Paracetamol4,000mg4,000m

In terms of efficacy, there is no clear benefit of the new OTC NSAIDs over ibuprofen. Certainly, for dysmenorrhoea, any of the OTC NSAIDs could be used. The OTC doses of all three available NSAIDs are roughly equipotent1,4 so ibuprofen may offer the best value for money.

However, it should be noted that some people can experience more benefit with one NSAID over another, as seen in rheumatoid arthritis. According to the BNF, only about 60 per cent of people will respond to any NSAID. In the remaining 40 per cent, those who do not respond to one NSAID may well respond to another.

It is also worth bearing in mind that the anti-inflammatory action of all NSAIDS can take at least a week (up to three weeks, according to the BNF) to be achieved, which is outside the recommended duration of use for many OTC products.

At OTC doses, ibuprofen is generally well tolerated and GI bleeding occurs less frequently than with aspirin. However, the same groups of people as discussed above with aspirin will be at greater risk of GI complications.

The Committee on Safety of Medicines has described ibuprofen as having the lowest risk of serious GI side effects and naproxen and diclofenac as having intermediate risk. According to the BNF, taking enteric coated formulations or taking tablets with food or milk does not completely remove the risk of GI effects.

Because many NSAIDs bind reversibly to COX-1 in the platelet, there is no demonstrable antiplatelet activity. An exception is naproxen, which appears to have a demonstrable antiplatelet effect.

There have also been reports of fluid retention, hypertension and oedema with NSAIDs so they should be used with caution in patients with cardiovascular disease or hepatic or renal impairment. This will be discussed further in the next CPD article.

NSAIDs are considered effective analgesics for mild to moderate pain, but they can cause serious adverse effects in some patients.

They are also involved in numerous drug interactions.

Drug combinations

Some OTC products contain more than one analgesic. For example, aspirin and paracetamol are used in combination in Anadin Extra (the low dose of paracetamol [200mg] in each tablet may work in synergy with aspirin as it does with tramadol in Tramacet).

The weak opioids codeine and dihydrocodeine are present in many products marketed for stronger pain relief. Other active ingredients are also found. For example, buclizine has been included in products for migraine for its antiemetic effect and diphenhydramine for pain that is causing the sufferer difficulty in getting to sleep.

Codeine and dihydrocodeine

Codeine and dihydrocodeine are available in OTC products at maximum doses of 25.6mg and 14.92mg, respectively. Codeine-containing products have been available for many years. The drug can be found combined with paracetamol, aspirin or ibuprofen in fixed combinations (8mg or 12.8mg codeine phosphate per dose unit). Products containing dihydrocodeine tartrate (7.46mg per dose unit) have been available for over 16 years.

The analgesia derived from codeine is largely due to its metabolism to morphine by cytochrome CYP2D6. However, about 10 per cent of Caucasians derive little benefit from codeine because, due a genetic polymorphism, they are unable to metabolise it.

Some drugs (eg, paroxetine, fluoxetine, quinidine) can affect metabolism through CYP2D6 inhibition. Dihydrocodeine seems not to be affected by this problem because its analgesic effect is, apparently, independent of CYP2D6 and this may be worth bearing in mind when recommending “stronger” painkillers.

On the other hand, despite the widespread availability of products containing these opioids, it is believed that the doses available in these products are too low to provide significant analgesic benefit over, for example, paracetamol alone.

However, typical opioid adverse effects such as nausea, vomiting and constipation can be experienced at these doses, especially in the elderly.5

An All Party Parliamentary Group in England has been assessing whether there is a case for ending OTC access to analgesics containing weak opioids because of their potential for abuse. In fact, there is a potential for misuse of many OTC analgesics (see Panel 4). A report is due by the end of the year (2008).

Panel 4: Misuse and abuse of over-the-counter analgesics

Misuse of a drug occurs if a person exceeds the recommended dose or duration of treatment. One of the concerns about self diagnosis and the use of OTC analgesia is that people can make an incorrect assumption about a condition, using an OTC analgesic inappropriately and later presenting to the GP with a serious condition that could have been treated earlier.

Medication overuse headache

One of the consequences of inappropriate use of OTC analgesics is medication overuse headache (previously known as analgesic rebound headache). Surprisingly, this condition only presents in patients using analgesics for headaches.

Chronic regular use of OTC analgesics (misuse) can, paradoxically, lead to headaches worsening and a spiralling of analgesic use. Rebound headache then occurs, which is likely to be followed by further analgesic use. The problem is believed to more common in women than men and it can also affect children.

Medication overuse headaches are often described as a dull generalised pain, which can be confused with tension headaches, and they are usually worse in the morning on waking. The underlying mechanism is not understood but may involve alteration in pain processing at a physiological level in addition to psychological factors.

Products containing paracetamol, aspirin, ibuprofen, codeine, dihydrocodeine or triptans have all been implicated.

Products containing two or more analgesics are more likely to induce analgesic rebound headaches. Products containing caffeine can also lead to the development of headaches as well as being potentially habit-forming.

Medication overuse headache may be overlooked and it is important to be vigilant if patients regularly present with headache. The widespread availability of OTC analgesics is one of the reasons why this condition is poorly identified.

Recurrent headache, especially if combination analgesics are used for more than 10 days a month, may indicate medication overuse headache. If this is suspected, the patient should be referred to his or her GP.

Abuse

One of the consequences of readily available medicines with the potential for habit forming is the risk of abuse. Abuse occurs if the patient takes the product for non-medical reasons, such as for a recreational effect.

Most people use OTC medicines responsibly and abuse is of concern in only a minority of users. Evidence suggests that there is no typical profile of a person likely to use OTC analgesics inappropriately.

Differentiating between a genuine or improper request or for an OTC analgesic is difficult, but thorough questioning and counselling will help to reduce the risk of misuse and potentially identify abuse. A range of strategies have been adopted by pharmacies to prevent inappropriate use of medicines, including refusing sales, removing products from display or simply not stocking them at all.

In 2005, the Medicines and Healthcare products Regulatory Agency (MHRA), reviewed the OTC status of products containing codeine and decided not to change their legal status to prescription-only because it was believed the reports of abuse were small.

Nonetheless, in an attempt to address the situation, the pharmaceutical industry voluntarily agreed to add warnings about addiction to packs of OTC products containing codeine and dihydrocodeine.

 

Caffeine

Caffeine is a constituent of many proprietary analgesics and it has been shown to produce enhanced pain relief, particularly in headache. The mechanism of action is believed to be improved absorption of the analgesic through lowering of gastric pH. If increased speed of onset of analgesia is desired, products containing caffeine may be worthwhile.

There are other pharmacological properties of caffeine that can influence analgesia. For example, caffeine-induced constriction of cerebral blood vessels may contribute to relief of headache and the central nervous system effects (notably an increased sense of well-being and elevated mood) may contribute to relief of general pain.

Doses of at least 100mg are needed to produce such effects and most preparations approach 130mg per dose. It is worth noting that a cup of tea or coffee will provide the same response.

The use of caffeine, however, is not without problems. Some patients may find the alerting effect unpleasant and there is a potential for abuse. Psychological and physical dependence can develop in individuals who consume caffeine regularly, leading to a withdrawal effect on discontinuation (see Panel 4).

Patients who already consume caffeine every day (in coffee, tea, soft drinks, etc) may experience adverse effects from consuming additional caffeine. Paradoxically, an effect of both too much caffeine and caffeine withdrawal is headache.

Other potential adverse effects include interference with sleep (avoid near bedtime), increases in blood pressure and aggravation of peptic ulcer disease.6

Topical analgesia

In view of the potential adverse effects of oral NSAIDs, topical analgesia should be considered before recommending them for mild musculoskeletal conditions.

Topical analgesics are indicated for a range of conditions, including muscular and rheumatic pain, fibrositis, sciatica, lumbago, sprains and strains. There are a variety of products and formulations available OTC, such as creams, ointments, gels and sprays. Active ingredients include diclofenac, felbinac, ibuprofen, ketoprofen, piroxicam and salicylic acid.

The efficacy of topical NSAIDs has been disputed, with the belief that any analgesic benefit is due to systemic absorption or a high incidence of placebo effect. However it has been shown that topical NSAIDs are both effective and safe in treating acute and chronic musculoskeletal conditions.7,8

There is no contraindication for using an oral and a topical NSAID. Although there is a 15 per cent absorption risk from topical products, at maximum OTC doses, combined use should not pose a problem in most people. Use of topical NSAIDs with prescription doses of oral NSAIDs increases the risk of adverse effects.

Although the absorption of topical NSAIDs is low and the potential for systemic adverse effects is small, people with asthma, an active peptic ulcer, renal impairment, or taking aspirin should consult their doctor before using these products.

Topical NSAIDs should not be used by pregnant or breastfeeding women unless on the recommendation of a doctor or by people who are known to be hypersensitive to aspirin or other NSAIDs.

Products containing counter-irritants or rubefacients (eg, salicylic acid esters) offer some mild analgesic action via vasodilation. For acute injuries that result in swelling and inflammation, such as sprains and strains, physiotherapists tend to prefer products that have a cooling effect to those that produce heat. Products that produce heat are preferred for the treatment of rheumatic pain or muscular stiffness.

Topical analgesics should be kept away from eyes and should not be used on broken skin.

Personalising recommendations

The second CPD article on this topic, to be published on 13 December 2008, will discuss cautions and contraindications for the different OTC analgesics and considerations for tailoring recommendations to the individual.

 

Andrew Dickman, MSc, MRPharmS, is a senior clinical pharmacist at the Marie Curie Palliative Care Institute, Liverpool, and the Liverpool Heart and Chest Hospital

 

References

1. Moore N. Diclofenac potassium 12.5mg tablets for mild to moderate pain and fever: a review of its pharmacology, clinical efficacy and safety. Clinical Drug Investigation 2007;27:163–95.

2. Milsom I, Minic M, Dawood MY, Akin MD, Spann J, Niland NF et al. Comparison of the efficacy of non-prescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen and placebo in the treatment of primary dysmenorrhoea: a pooled analysis of five studies. Clinical Therapeutics 2002;24:1384–1400.

3. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. New England Journal of Medicine 1991;325:87–91.

4. Bandolier. Oxford league table of analgesics in acute pain. Available at www.medicine.ox.ac.uk (accessed on 26 November 2008).

5. Zhang WY, Li Wan Po A. Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain — a meta-analysis. Clinical Pharmacology and Therapeutics 1996;214:261–82.

6. Feinstein AR, Heinemann LA, Dalessio D, Fox JM, Goldstein J, Haag G et al. Do caffeine-containing analgesics promote dependence? A review and evaluation. Clinical Pharmacology and Therapeutics 2000;68:457–67.

7. Mason L, Moore RA, Edwards JE, Derry S, McQuay HJ. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BMC Musculoskeletal Disorders 2004;19;5:28.

8. Mason L, Moore RA, Edwards JE, Derry S, McQuay HJ. Topical NSAIDs for acute pain: a meta-analysis. BMC Family Practice 2004;17;5:10.

Citation: The Pharmaceutical Journal URI: 10040592

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