A Wee bit o' Pain

Pain is...

a) According to the US Marines 'weakness leaving the body'.

b) According to medicine 'an unpleasant sensation in response to a noxious stimuli'.

c) According to Winnie the Pooh, being separated from his friend - 'If you live to be 100, I hope I live to 100 minus 1 day, so I never have to live without you.'


Although it is contentious as to which is the correct answer, b) probably serves best to get mine, and your, bioscience juices pumping.


Pain can be acute or chronic, and appropriate (brought on by a noxious stimulus) or inappropriate (not caused by any identifiable stimulus).  Management of pain comes into many aspects of medicine, and analgesics are a major part of this.


Types of Pain

Prescribing Analgesics

The word analgesia comes from Greek origins:

  • an = without
  • algesia = pain


Analgesics have been around for centuries, with the business of making people 'without pain' bringing in the dollar bills to many a pharmaceutical company.  However, with that said, how do we prescribe for pain?


In the acute care section there is a Pain Management article, so this overview will look at the prescribing elements.  Prescribing for pain requires looking at the whole picture of the clinical case; helpfully there is an ABCD guide:


A = Acute or chronic?

Mangement of acute pain requires prescription of enough analgesic to alleviate pain; however this can range from giving paracetamol for a headache in general practice, to morphine for suspected myocardial infarction in A&E.  Management of chronic pain may mean increasing the dose of a drug already prescribed, or adding on a new analgesic.


B = How bad is the pain?

It's simple: the worse the pain, the stronger the analgesic required.  The WHO (World Health Organisation) developed a protocol in 1986 for managing pain in cancer patients.  This has been developed over the years and now takes the form of the analgesic ladder (see diagram below).  Although originally for cancer pain, it is widely applied to the management of pain throughout medicine, especially of chronic pain.  It provides guidance and a step-wise approach to prescribing based on the severity of the pain.

On referring to an adjuvant analgesic, it means the drug would be a weak analgesic on its own, but when given with other pain medication, it enhances analgesia.


C = What is the condition underlying pain?

Often there are conditions for which specific analgesics are prescribed.  For example, mefenamic acid is an NSAID prescribed for dysmenorrhoea, as it decreases uterine contractions as well as acting as a typical NSAID.


D = Drug allergies, impairments preventing prescription of certain drugs.

This is a really important aspect of prescribing any drugs, including analgesics.  For example, NSAID's shouldn't be prescribed to asthmatics due to increased leukotriene production (see below).  You also need to take into account previous responses to analgesics - for example, if a patient did not respond to codeine for their sciatica previously, there is not much point prescribing it for future episodes.  It is always worth ascertaining what drugs the patient has already tried to relieve the pain.


World Health Organisation Analgesic Ladder

NSAID's (Non Opioid)

Non-steroidal Anti-Inflammatory Drugs are amongst the most commonly prescribed drugs around.  These drugs have three things in common: analgesic, anti-inflammatory and anti-pyretic properties.  One of the most famous of these NSAID's is aspirin, which was discovered at the same time as heroin by the same man.



NSAID's exert their action on the arachidonic acid pathway.  This pathway is found within cells.  The cyclooxygenase (COX-1 and COX-2) enzymes are  inhibited by NSAIDS.  COX-1 is normally constitutionally active in most tissues (active all the time at a basal level), providing housekeeping chemicals (chemicals that keep the body running normally day to day) that coat the stomach lining, cause platelet aggregation and aid kidney function.  COX-2 is inducible within inflammatory cells, meaning that it will be activated when there is a change in the cell membrane leading to its production of inflammatory chemical mediators.


Aspirin has a very slightly different mechanism of action to other NSAIDs.  While the majority of NSAIDs are reversible inhibitors of COX enzymes (i.e. they temporarily bind to the enzyme, preventing its normal function), aspirin is an irreversible inhibitor.  This means it binds permanently, and its block on COX activity can only be overcome by synthesising new enzyme to replace the inactivated molecules.


Aspirin has also been recognised as having added pharmacological potential as an anti-platelet due to its effect on reducing thromboxane.  While some other NSAIDs also reduce thromboxane, aspirin's unique pharmacology makes it the only NSAID to be clinically effective.  It may also be implicated in reducing colorectal cancer and Alzheimer's Disease.


Below is a diagram showing the Arachadonic Pathway:


Arachidonic Acid Pathway

Image showing the arachidonic acid pathway


  • COX-2 inhibitors & Diclofenac increase thrombotic events

-Not for at risk patients unless needed.

  • Peptic Ulceration (inhibition of Prostagladins)
  • Liver Disorders
  • Reduced Kidney Function
  • Skin Reaction
  • Bronchospasm



Aspirin rapidly hydrolysed in liver to salycilate. Oxidised and excreted in urine.

Variable half lives.  



-Analgesia in mild to moderate pain

-Anti-inflammatory & antipyriectic pain.


Examples of NSAID's

Paracetamol (Non Opioid)

Paracetamol (acetaminophen in the USA) is the most common over the counter analgesic with both analgesic and antipyretic properties.  However, it is not considered an anti-inflammatory as it doesn't cut the mustard in that role.  Fortunately it also doesn't cause the GI side effects of NSAIDs. In overdose it is highly toxic as one of its metabolites, NABQI, causes pesky free radical formation which kills hepatocytes.



    Paracetamol is thought to inhibit prostaglandin (PGE) formation, though how it does this is anyone's guess.  Recent evidence suggests that paracetamol may act as a pro-drug, being converted within the body to a substance that works upon cannabinoid receptors.  This is thought to explain some of the behavioural and addictive effects the drug has...!



      • Care in renal impairment.
      • Skin Reaction

      - Relatively rare

      • Hepatotoxicity

      -In overdose can lead to liver failure



        Highest concentration in blood after 30-60minutes.

        Metabolised in the liver.




        An opioid is anything that produces morphine-like effects.  Morphine is the active element of opium, and the name comes from Morpheus - the Greek God of Dreams.  Morphine was quickly discovered to be both addictive and toxic, which lead to the manufacture of heroin as an alternative drug without these unwanted side effects.  Unfortunately, this was a load of baloney.


        Opioids are either morphine analogues (similar structure to morphine) or synthetic derivatives (unrelated structure).



          There are three major opioid receptors: μ, δ and κ.  These have varying locations within the nervous system.  All are responsible for the analgesic effects but also are responsible for individual effects:  

          - μ - general analgesia, respiratory depression, euphoria, sedation, dependence, vomiting, urinary retention, reduced bowel peristalsis

          - δ - spinal analgesia, some general analgesia

          - κ - General analgesia, sedation, dyspnoea, psychoactive, miosis, respiratory depression, euphoria, dysphoria

          Different opioids have varying selectivity for the different receptors


          SIDE EFFECTS

            • Respiratory Depression
            • Depression of Cough Reflex
            • Tolerance & Dependence

            - Tolerance after 24 hours

            - Physical (few days) and psychological (years) dependence in chronic use

            • Constipation
            • Urinary Retention
            • Nausea & Vomiting

            - Antiemetic usually prescribed along with the opioid.

            • Pupil Constriction
            • Bronchospasm & Hypotension

            - due to systemic opioids inducing increased histamine release from mast cells.



              Plasma half life 3-6 hours for morphine analogues, but does vary between individuals.

              Metabolised by the liver.



                -Usually in severe pain, although codeine and dihydrocodeine are given in mild to moderate pain.

                -Opioids are usually not useful in neuropathic pain due to decreased opioid sensitivity in this pathology.

                -Acute & chronic pain.


                Morphine Analogue Examples

                Synthetic Derivative Examples


                Neuropathic pain is often tricky to manage, with opioid analgesics often unable to aid it.  Other drugs have become implicated in dealing with this kind of pain such as the ones below


                Tricyclic Antidepressants

                  e.g. amitriptyline

                  Reduce noradrenaline reuptake



                    e.g. carbamazepine & gabapentin

                    Affect ion channels to reduce transmission of nociceptive signals.


                    Local Anaesthetics

                      e.g. lidocaine.

                      Block spontaneous discharging nerve terminals.



                      Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R. and Leone, S.  (2006).  Paracetamol: new vistas of an old drug.  CNS Drug Reviews. 12(3-4):250-275.

                      Rang, H. P, Dale, M. M., Ritter, J. M. and Flower, R.  (2007).  Rang & Dale's Pharmacology.  London.  Churchill Livingstone.  Section 2 & 4

                      British National Formulary (March 2011).  Royal Pharmaceutical Society, London.

                      World Health Organisation.  WHO's Pain Relief Ladder.  Geneva, World Health Orginisation.  Accessed on 11/03/11 at http://www.who.int/cancer/palliative/painladder/en/


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