Non-opioid analgesics

Overview of non-opioid analgesics.

Non-opioid analgesics, according to the WHO pain ladder, include various substance classes with different mechanisms of action. In addition to the classical NSAIDs and selective COX-2 inhibitors, substances such as paracetamol; and metamizole are also members of this group. Metamizole is prohibited in several European countries due to potential serious side effects.

Non-opioid analgesics can be classified due to their chemical characteristics as acid (NSAIDs = non-steroidal anti-inflammatory drugs such as ASA, ibuprofen, diclofenac, naproxen) and non-acid (paracetamol, metamizole).

The common mechanism of action of these substances is their effect on prostaglandin synthesis.


Non-opioid analgesics: NSAIDs

NSAIDs have an effect on the prostaglandin synthesis.

All NSAIDs have the same mechanism of action inhibiting the enzyme cyclooxygenase (COX) and consequently prostaglandin synthesis.

  • By inhibiting prostaglandins NSAIDS reduce tissue inflammation and pain
  • NSAIDs mainly act peripherally
  • Most NSAIDs are relatively non-selective, inhibiting both COX-1 and COX-2 enzymes in a ratio that varies from drug to drug
  • As their name suggests, selective COX inhibitors are more potent at the COX-2 enzyme (selective COX-2 inhibitors)
  • Caution is required when using NSAIDs because of certain common side effects
  • These include gastrointestinal irritation and risk of gastrointestinal bleeding, renal toxicity, potential drug -drug interactions
  • Some selective COX -2 inhibitors have also been found to have cardiovascular side effects such as myocardial infarction, stroke and elevation of blood pressure
  • NSAIDS must be used with caution in older patients with impaired renal function and heart failure

NSAID Use in Chronic Pain

NSAID-induced gastric mucosal ulcers

There is evidence that NSAIDs are prescribed in place of opioids for non-cancer pain especially in some south European countries – 68 % and 49 % in Italy and Spain.1

  • The EMEA recommends that the lowest effective dosage and short-term use of these agents is to be preferred.2
Breivik H et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006; 10: 287-333
Schnitzer et al. Update on guidelines for the treatment of chronic musculoskeletal pain. Clin Rheumatol (2006) 25 (Suppl 1): S22–S29


Other non-opioid analgesics: Paracetamol and Metamizole

Paracetamol and metamizol predominantly inhibit central prostaglandin synthesis.

Paracetamol must be set apart from NSAIDs because of their predominantly central prostaglandin synthesis inhibition. Their mechanism of action has still not been fully explained.

Paracetamol is an aniline derivative and is used widely as an analgesic and antipyretic, but it has no significant anti-inflammatory effects. Paracetamol is associated with risk of toxic liver damage at high doses.

Metamizole acts by inhibiting central prostaglandin synthesis and has other, not yet fully explained mechanisms of action. In addition to its analgesic, antipyretic and slightly anti-inflammatory effect, metamizole also has an antispasmodic action. Side effects include risk of agranulocytosis after intravenous injection. Metamizole is prohibited in several European countries due to potential serious side effects.


Opioid analgesics

Classification of opioids according to their analgesic potency

Opioids are broadly subdivided in to weak and strong agents.

Opioids are effective in managing nociceptive pain. The mainstay of use of opioids is in management of postoperative and cancer pain.

However it is undisputed that patients with chronic non-cancer pain can benefit from opioid therapy.

WHO classification

  • Weak opioids (e.g. tramadol, codeine)
  • Strong opioids (e.g. morphine, oxycodone, fentanyl)


  • Mainly effective in nociceptive pain
  • Less effective in chronic states
  • Only partially effective in neuropathic pain
Davis MP. What is new in neuropathic pain? Support Care Cancer 2007;15:363-372
Ballantyne JC, MAO J. Medical progress opioid therapy for chronic pain. NEJM 2003;349 (20):1943-1953.


Opioids – Mechanism of Action

Sites of action

Opioids act at two sites:

  • They reduce pain signal transmission by activating pre-synaptic opioid receptors. This leads to reduced intracellular cAMP concentration, decreased calcium ion influx and thus inhibits the release of excitatory neurotransmitters (glutamate, substance P).
  • At the post-synaptic level, opioid-receptor binding evokes a hyperpolarisation of the neuronal membrane which decreases probabilty of the generation of an action potential.

Opioids function as inhibitory transmitters of the descending inhibitory pathway. They also affect other supraspinal structures of pain processing, in particular the thalamus and limbic system altering the emotional assessment of pain, i.e. pain is still perceived, but is no longer felt as being unpleasant or threatening.

The nervous system comprises neurons of many different types which differ in size, shape, function and the chemical nature of the neurotransmitters released from their terminals to carry information to other neurons. Morphine, by an action on μ-receptors, inhibits release of several different neurotransmitters including acetylcholine, glutamate and substance P.


Opioid-induced (side-)effects

Opioid-induced side-effects can be subdivided into central and peripheral effects

Common side-effects of opioids are nausea and vomiting particularly at the start of treatment.

Opioids are associated with an increased risk of respiratory depression especially in situations of overdose and concomitant use of CNS depressant drugs.

These drugs are associated with sedative/hypnotic effects.
Constipation is a commonly occurring side-effect of opioids and does not tend to diminsh with time on treatment.

Other side effects can include cholestasis and micturition disorders, urticaria, pruritus, bronchospasms in asthmatic patients, hypotension (orthostatic dysregulation) and decrease in heart rate.

Long-term use of opioids can also be associated with the development of abnormal sensitivity to pain (hyperalgesia, allodynia)1

Ballantyne JC, Mao J. Medical Progress opioid therapy for chronic pain. NEJM 2003; 349(20):1943-1953


Reuptake inhibitors: Tricyclic Antidepressants (TCA)

Neuronale reuptake of inhibitory neurotransmitters

Antidepressant substances which are commonly used in treatment of neuropathic pain mainly include tricyclic antidepressants (TCA) and selctive noradrenaline reuptake inhibitors (SNRIs).
As a group, these agents all act by affecting the neuronal reuptake of key neurotransmitters involved in pain signaling.
One such group of drugs are the TCAs, which inhibit neuronal reuptake of noradrenaline and serotonin (5-HT). They may be effective in neuropathic pain, migraine and tension headache.1
Drug drug interactions with drugs such as cimetidine, phenothiazine and some antiarrhythmic drugs may occur.2
TCAs must be used cautiously in patients with a history of cardiovascular disease, glaucoma, urinary retention, or autonomic neuropathy.

Side effects:

  • Anticholinergic effects: Dry mouth, constipation, accommodation disorders, mydriasis (glaucomatous attack!), micturition disorders
  • Cardiovascular:Orthostatic dysregulation, hypotension, syncope, AV asequence, arrhythmia, QT prolongation, tachycardia
  • Central nervous: Sedation, drowsiness, insomnia, increased appetite
  • Sexual disorders
  • Impaired liver function
Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci; 2001;26(1):30-36
Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524-34.


Selective Serotonin and Noradrenaline Reuptake Inhibitors

Neuronale reuptake of inhibitory neurotransmitters

The selective serotonin (5-HT) and noradrenaline reuptake inhibitors (SNRIs) selectively inhibit the reuptake of noradrenaline and serotonin from the synaptic cleft.

Similar to TCAs, the resulting increased transmitter concentration intensifies the descending pain inhibition pathway.

Unlike the TCAs, the SNRIs have little affinity for adrenergic, cholinergic or histaminergic receptors and so are not associated with side effects linked with inhibition of these systems.

SNRIs are better tolerated than TCAs but may only have moderate efficacy in pain management.1

Side effects include nausea, vomiting, constipation, somnolence, dry mouth, increased sweating, loss of appetite, weakness.

Attal N, Cruccu G, Haanpää M, et al.; EFNS Task Force. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13:(11)53-69



Different mechanisms of action

Anticonvulsant agents belong to a broad group of drugs that are ion channel blockers and inhibit neuronal excitation and stabilize nerve membranes through the blocking of ion channels in the CNS.
Anticonvulsants were originally developed for the treatment of cerebral seizures.

With regard to pain therapy, the main indication for anticonvulsants is shooting neuropathic pain (e.g., trigeminal neuralgia, postherpetic and other neuralgias).

Gabapentin has been shown to be effective in neuropathic pain and thus recommended as first line analgesic in this indication.1,2 It binds to a subunit of presynaptic voltage-dependent calcium channels. The binding reaction reduces release of pre-synaptic transmitters. As a consequence, an analgesic effect occurs.

Pregabalin is another anticonvulsant being used and recommended for first-line treatment in neuropathic pain conditions.1 It provides its analgesic effect by interacting with special N-type calcium channels and – as a consequence - regulating neurotransmitter release. Pregabalin does not undergo hepatic metabolism and has a low risk of drug-drug interaction.

Carbamazepine blocks calcium and sodium channels and is also indicated for neuropathic pain conditions2, but is associated with more side effects than pregabalin and gabapentin including fatigue, nausea, vomiting, arrhythmia, double vision, pruritus.

Attal N, Cruccu G, Haanpää M, et al.; EFNS Task Force. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13:1153-69.
Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524-34


Topical Analgesics

Topical analgesics

Main categories of topical analgesics include:
  • Rubefacients: traditional formulations based on salicylate and nicotinate esters, capsaicin and capsicumextracts and derivatives
  • NSAIDs: diclofenac, felbinac, ibuprofen, ketoprofen, piroxicam, naproxen, flurbiprofen and other NSAIDs
  • A miscellaneous group: including benzydamine, mucopolysaccharide polysulphate, salicylamide and cooling sprays

Topical analgesics are widely available – many without prescription – in a variety of application forms. Some are rubbed onto the skin to produce pain relief, but there are also plasters available on the market.

There is a number of possible definitions for topical analgesics since many different applications fall under this category.


Local anaesthetic: Lidocaine 5% medicated plaster

Two mechanism of action

Local anaesthetics are also thought to exert their actions through blocking of ion channels in cell membranes. Local anaesthetics such as lidocaine may be used peripherally for symptomatic relief of neuropathic pain.

The lidocaine plaster develops its analgesic efficacy based on two different principles:

  1. The device as such offers an immediate cooling and soothing mechanical protection against painful as well as non-painful stimuli. By protecting e.g. against the painful rub of clothing on the skin (allodynia), the plaster may contribute significantly to improving patients' quality of life.
  2. Topical lidocaine effects on the membranes of peripheral endings of A- and C- nerve fibres where it blocks mainly pathologically over-excitable sodium channels. This blockade inhibits sodium ion influx which is needed to generate an action potential transmitting a signal towards to central nervous system. As a consequence of the targeted blockade the neuronal membrane is stabilised, ectopic discharges are reduced and peripheral nociception is inhibited (local analgesia). As a long-term consequence, reduction of peripheral input may counteract on central sensitisation.

The 5% medicated lidocaine pflaster is indicated for neuropathic pain following a herpes zoster.infection (post zoster neuralgia).1

SPC Versatis, 2010


Quick check

Which of these statements is true regarding the clinical role of NSAIDs in managing pain? Select the correct response.
NSAIDs act on nociceptive pain and are not effective for the management of chronic neuropathic pain.
NSAIDs are effective on chronic neuropathic pain but not nociceptive pain.
NSAISs have few side effects and therefore are ideal for use in long-term pain management.
Which of these statements is right?
Opioids only affects supraspinal structures of pain processing, in particular the thalamus and limbic system.
By binding at presynaptic opioid receptors, opioids inhibit the release of excitatory neurotransmitters via decreased intracellular cAMP concentration as well as decreased calcium ion influx.
At postsynaptic level, opioids evoke a depolarisation of the neuronal membrane which decreases probability of the generation of an action potenial.


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