Non-prescription (OTC) oral analgesics for acute pain- an overview of Cochrane reviews

  • Protocol
  • Overview



This is the protocol for a review and there is no abstract. The objectives are as follows:

To examine published Cochrane reviews for information about the efficacy of pain medicines available without prescription in the UK. Licensing of analgesics available without prescription in the UK is broadly similar to that in the USA, Australia, and much of Europe. It would also be our aim to provide sufficient information for individuals to work out for themselves what the efficacy may be for specific over-the-counter (OTC) products not included by name in the review.


Description of the condition

Acute pain is experienced from time to time by almost everyone and is defined as short-term pain of less than 12 weeks duration. It may be due to tissue damage or nerve injury, or both, as a result of injury (e.g. sprains and strains, falls), surgery, or to a temporary or intermittent 'malfunction' of a body system (e.g. dysmenorrhoea (period pain), constipation), or to some form of headache (e.g. tension headache). It is frequently a manifestation of inflammation and sometimes swelling, especially in joints and muscles. By definition, it is not expected to continue indefinitely, even if not treated, but it can have a significant impact on ability to function normally.

Studies to determine the efficacy of analgesics in acute painful conditions are most commonly carried out in patients who are experiencing postoperative pain. The methods have been standardised over many years and the study design has proved to be robust (McQuay 2012). Trials have to be randomised and double-blind. Typically, in the first few hours or days after an operation, patients develop pain that is moderate to severe in intensity, and will then be given the test analgesic (the intervention) or a placebo. Pain is measured using standard pain intensity scales immediately before the intervention and then afterwards using pain intensity and pain relief scales, usually over the following six hours. Pain relief of half the maximum possible pain relief or better (at least 50% pain relief) has become the standard outcome. For patients given rescue medication it is usual for no additional pain measurements to be made, and for all subsequent measures to be recorded as initial pain intensity or baseline (zero) pain relief (baseline observation carried forward). This process ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention.

Non-prescription analgesics for migraine headache will be covered in a different Cochrane review.

Description of the interventions

The aim is to try and assess relative efficacy of drugs like aspirin, paracetamol (acetaminophen), ibuprofen, diclofenac, naproxen, and other drugs alone, and in combinations with each other, with weak opioids like codeine, or with caffeine.

There is a bewildering variety of analgesics available without prescription in various parts of the world. They include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) (such as aspirin and ibuprofen), and opioids (usually codeine), as well as numerous 'complementary therapies' and 'herbal' products. They may be available in different formulations, such as standard tablets, fast-acting tablets, effervescent powders, or liquids, and are frequently combined with each other, or with other products such as caffeine. Packaging and branding can make it difficult to identify similar products or to compare them.

Many of these analgesics can be bought from open shelves in pharmacies, supermarkets, and convenience stores, without any consultation with a doctor or checking by a pharmacist, while some are not displayed on open shelves and require some form of authorisation from a pharmacist before they can be sold. Regulations regarding the availability of these products vary between countries.

There are a number of websites that can provide information on analgesics available without prescription. In the UK this is the Proprietary Association of Great Britain ( For Europe, a searchable database is available from the European Self-medication Industry (, and for countries outside Europe at the website of the World Self-medication Industry (

How the intervention might work

NSAIDs reversibly inhibit the enzyme cyclooxygenase (prostaglandin endoperoxide synthase or COX), now recognised to consist of two isoforms, COX-1 and COX-2, mediating production of prostaglandins and thromboxane A2 (Fitzgerald 2001). Prostaglandins mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive (pain) processes. However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cyclooxygenase-dependent prostanoid formation (Hawkey 1999). Aspirin is a special case, in that it irreversibly blocks COX-1. It also has good antipyretic (fever reducing) properties.

Paracetamol lacks significant anti-inflammatory activity, implying a mode of action distinct from that of NSAIDs. Despite years of use and research, however, the mechanisms of action of paracetamol are not fully understood. Paracetamol has previously been shown to have no significant effects on COX-1 or COX-2 (Schwab 2003), but has recently been considered as a selective COX-2 inhibitor (Hinz 2008). Significant paracetamol-induced inhibition of prostaglandin production has been demonstrated in tissues in the brain, spleen, and lung (Botting 2000; Flower 1972). A 'COX-3 hypothesis' wherein the efficacy of paracetamol is attributed to its specific inhibition of a third cyclooxygenase isoform enzyme, COX-3 (Botting 2000; Chandrasekharan 2002; PIC 2008) now has little credibility and a central mode action of paracetamol is thought to be likely (Graham 2005).

Codeine is an opioid which is metabolised in the liver to the active compounds morphine and morphine-6-glucuronide. Opioids bind to specific receptors in the central nervous system (CNS), causing reduced pain perception and reaction to pain, and increased pain tolerance. In addition to these desirable analgesic effects, binding to receptors in the CNS may cause adverse events such as drowsiness and respiratory depression, and binding to receptors elsewhere in the body (primarily the gastrointestinal tract) commonly causes nausea, vomiting, and constipation. In an effort to reduce the amount of opioid required for pain relief, and so reduce problematic adverse events, opioids are commonly combined with non-opioid analgesics, such as paracetamol.

While there may be other components in some non-prescription analgesics, these are usually present infrequently, and at doses too low to have any major impact. An exception is caffeine, which has been shown to add to analgesic effects in acute pain, in conjunction with conventional analgesics, and at caffeine doses of 100 mg or above (Derry 2012).

Why it is important to do this overview

This review is intended to provide information to consumers about non-prescription oral analgesics for treating acute pain conditions like toothache, period pains, headache, or acute musculoskeletal problems like strains and sprains. Many products are available, but there is little information about their relative efficacy.

Scanning the pharmacy online databases will determine how many formulations are available to treat mild headache, joint and muscle pain, dental, back, and period pain. The amount of high quality information about the efficacy of these analgesics is limited. Although Cochrane reviews are intended for use by consumers as well as healthcare providers and commissioners, there is to date no overview that directly addresses consumer issues relating to acute pain treatments that can be obtained without a prescription and their effectiveness. The consumer is faced with a variety of different pain relieving medicines, at different amounts per tablet, sometimes alone and sometimes with other ingredients available; this makes choosing a product rather difficult for the consumer.

A broad range of analgesics is available without prescription in many parts of the world. This review is intended to cover most of the less costly analgesics available almost anywhere in the world.


To examine published Cochrane reviews for information about the efficacy of pain medicines available without prescription in the UK. Licensing of analgesics available without prescription in the UK is broadly similar to that in the USA, Australia, and much of Europe. It would also be our aim to provide sufficient information for individuals to work out for themselves what the efficacy may be for specific over-the-counter (OTC) products not included by name in the review.


Criteria for considering reviews for inclusion

We will include reviews that provide information on any drug, dose, or formulation that matches the content of analgesic products available without prescription in the UK. In the UK, the usual recommended dose uses two tablets. A list of available medication will be drawn up by two review authors (YR and LT) from the Internet sites of Boots ( and Lloyds Pharmacy ( We will limit the overview to medication available in the UK because it is almost impossible to know with certainty what is available in other parts of the world. However, for completeness, we will examine online pharmacy websites in the USA (Walgreens, CVS), Canada (Shoppers Drug Mart), and Australia (Guardian, Terry White Chemists) to check on any major drugs or combinations not available in the UK. We will specifically include dipyrone, which while not available in any of the countries listed, is available without prescription in many parts of the world.

Medicines covered in the review will be applicable to all parts of the world, and will include the most commonly used.

Included reviews will be Cochrane reviews of randomised controlled trials (RCTs) carried out to high methodological standards, using validated methods and outcomes of interest to patients. Each medicine will be compared with placebo to allow indirect comparison between them. It is anticipated that included reviews will be of medication used in acute postoperative pain, where study participants have established pain of moderate to severe intensity before treatment. In most circumstances it is considered appropriate to extrapolate these results to acute pain generally. The outcome must be of direct relevance to patients, namely no worse than mild pain, or at least 50% of maximum pain relief (McQuay 2012; Moore 2013a).

It is highly likely that the bulk of studies contributing information will have been performed in pain following third molar extractions, as demonstrated in a Cochrane overview (Moore 2011).

Search methods for identification of reviews

Two review authors will independently search theCochrane Database of Systematic Reviews for relevant reviews. All relevant reviews are known to the authors and are published by the Pain, Palliative and Supportive Care Group. Titles published by other groups with an interest in acute pain (e.g. Oral Health, Anaesthesia) will be examined for relevance.

Data collection and analysis

Two review authors will independently select reviews for inclusion, carry out assessment of methodological quality, and extract data. Any disagreements will be resolved by discussion, involving a third review author if necessary.

Selection of reviews

Included reviews will assess RCTs evaluating the effects of a single oral dose of analgesic given for relief of moderate to severe postoperative pain in adults, compared to placebo, and include:

  • a clearly defined clinical question;

  • details of inclusion and exclusion criteria;

  • details of databases searched and relevant search strategies;

  • patient-reported pain relief; and

  • summary results for at least one desired outcome.

Data extraction and management

We will extract data from the included reviews using a standard data extraction form, using original study reports only if specific data are missing.

We will collect information on the following:

  • number of included studies and participants;

  • drug, dose, and formulation (if formulation is an issue).

We will extract information on relative risk (RR) and numbers needed to treat to benefit (NNT), to prevent an event (NNTp), and to harm (NNH) or calculate these for the following outcomes:

  • ≥ 50% maximum pain relief over four to six hours (patient-reported): this outcome encapsulates both degree of pain relief and duration of the effect, and is a dichotomous measure of success over a defined period following drug ingestion;

  • success and failure rates, where success (as a percentage of the maximum possible) was calculated from the drug-specific effect and maximum possible effect (Moore 2013b);

  • patients suffering one or more adverse events.

Assessment of methodological quality of included reviews

We will assess the methodological quality of included reviews according to the criteria specified in the 'assessment of multiple systematic reviews' (AMSTAR) measurement tool (Shea 2007) for rigorous methodological quality.

Each review should:

  1. provide an a priori design;

  2. carry out duplicate study selection and data extraction;

  3. carry out a comprehensive literature search;

  4. include published and unpublished studies irrespective of language of publication;

  5. provide a list of studies (included and excluded);

  6. assess and document the scientific quality of the included studies;

  7. use the scientific quality of the included studies appropriately in formulating conclusions;

  8. use appropriate methods to combine the findings of studies; and

  9. state conflicts of interests.

Data synthesis

We will use information on the selected efficacy outcomes to draw up comparisons of analgesic efficacy, using indirect comparison of different drugs from almost identical clinical trial conditions, with placebo as a common comparator (Glenny 2005; Song 2003). A minimum of 200 participants are required in any comparison of an intervention with placebo (Moore 1998).

Comparative results at recommended doses will be expressed as:

  1. participants achieving at least 50% maximum pain relief, as a percentage, and as NNT for at least 50% maximum pain relief over four to six hours, compared with placebo;

  2. success and failure rates;

  3. participants experiencing at least one adverse event.

We will list marketed products for which no good quality evidence is available.


The Oxford Pain Relief Trust provides institutional support for this work.

Contributions of authors

YR and LT will search for medicines available without prescription. SD and CD will extract data from Cochrane reviews relating to drug efficacy. RAM and PW will check data extraction and assessment. All authors will be involved with developing the manuscript.

Declarations of interest

None declared.

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK.

    Institutional support

External sources

  • No sources of support supplied