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There is a very strong and useful literature to guide analgesic use. Prescribers should be aware of the analgesic ladder and properties of all the common agents used. It is an area where subjective responses may tend to override objective analysis and so become a challenge for rational prescribing. That some analgesics can promote addiction is a futher complication.


The properties of extracts of the opium poppy (Papaver somniferum) containing opioids were known in prehistory with Sumerian artifacts (ca. 4000 BC) for example illustrating the plant with a descriptive term which has been translated as the "joy plant". Documented use of white willow (Salix alba) containing salicylic acid also dates back to at least 3000 BC. These discoveries were several times lost and then reentered the written record of western medicine. In due course technology allowed these plant extracts to be examined and characterised. Morphine was the first plant alkaloid thus isolated in December 1804 by Friedrich Sertürner and is now known to be synthesized in animals including man as a neurotransmitter. It was first offered as an analgesic in 1817 with effective commercialisation by Merck in 1827. Phenacetin was successfully introduced in 1887 as the first successful synthetic oral non-opioid analgesic. Acetanilide had preceded it to the market by one year in 1886 but had unacceptable prodrug toxicity (it is actually metabolised to paracetamol). Diacetylmorphine (heroin) was synthesized in 1874 and brought to market by Bayer in 1898. The synthesis of aspirin in 1853 and its marketing again by Bayer in 1899 was followed by paracetamol in 1956 and ibuprofen in 1962. Essentially since 1962 all the developments in analgesia can be regarded as detailed fine print, but rather important fine print at that, including the withdrawal of a number of toxic analgesics such phenacetin (as late as 1983 in the USA) and failure of a number of me too improvements such as benoxaprofen and rofecoxib. The fine print includes a fairly good understanding of the mechanisms of action but a still far from complete understanding of the comparative properties of the many analgesic drugs now available. For example co-proxamol which contains dextropropoxyphene was withdrawn in the UK in 2005 because of its toxicity in overdose relative to its other properties and it is only recently that a signal as to the relative toxicity of codeine compared to some other opioid analgesics has emerged.

Clinical Use


The sole indication is pain but not all pain is the same. This requires a much fuller understanding of the pharmacology of analgesia than this article presently offers. For example neuropathic pain such as from trigeminal neuralgia (carbamazepine) or diabetic neuropathy (amitriptyline/duloxetine) have different agents of choice that are not classic analgesic agents.

Clinical Differences

The agents used have very important clinical differences, even within the same class. Safety can vary as can tolerablity.

Clinical Issues

Important issues are:

  1. Pain control can be very challenging as it is a perception with major impact on quality of life
  2. Many agents were developed and found useful without evidence from comparative clinical trials
  3. Long term effectiveness has proved to be different to short term effectiveness
  4. Much use is by analogy
  5. Safety
    • In the absence of data or with the distortion of how data is presented relatively safety can be hard to understand
      • Rofecoxib is an example of a formally widely used drug where distortion in how data was presented in safety domains was significant
      • The more popular NSAIDs have fair RCT data as to mortality and cardiovascular risk which is consistent with the epidemiological data[1]. In terms of both deaths from any case and cardiovascular risk naproxen appears to be the safest.
      • Only recently has epidemiological data become available with oral opioids such as codeine that causes concern with their safety in typical use due to overdose[2], all cause mortality relative to NSAIDs[3] and variable fracture and mortality risk within the class[4]. The data has added concern as if the relative risk of death with NSAID use compared to no use is increased by about 1.7 times, this means weak opioid use might be associated with a trebling in all cause mortality when the opioids are used for arthritis pain.

Special advice

Recently some of the literature used to justify complex pain and post-operative pain regimes has been called into question as a result of research fraud. This is especially but not only in the context of so called multimodal analgesia including the combination of celecoxib and pregabalin [5]. Other withdrawn papers by Scott S Rubins have addressed issues such as intraarticular ketorolac and morphine, controlled release oxycodone, brachial plexus anaesthesia with verapamil and/or morphine, morphine, celecoxib and rofecoxib after spinal fusion surgery, intravenous regional anesthesia with lidocaine and ketorolac, complex regional pain syndrome threated with intravenous regional anesthesia with clonidine and venlafaxine XR in the prevention of postmastectomy pain syndrome,



This article is a work in progress. Please feel free to contribute to it.


This category has the following 5 subcategories, out of 5 total.