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.
All NSAIDs have the same mechanism of action inhibiting the enzyme cyclooxygenase (COX) and consequently prostaglandin synthesis.
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
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.
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.
Opioids act at two sites:
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.
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
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.
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.
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.
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 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:
The 5% medicated lidocaine pflaster is indicated for neuropathic pain following a herpes zoster.infection (post zoster neuralgia).1