Commonly used adjuvants in pain management

In adults, the most commonly prescribed adjuvants for neuropathic and nociplastic pain are:

• gabapentinoids—gabapentin, pregabalin
• tricyclic antidepressants (TCAs)—amitriptyline, nortriptyline
• serotonin and noradrenaline reuptake inhibitors (SNRIs)—duloxetine, venlafaxine.

In children and adolescents, there is insufficient evidence that gabapentinoids, TCAs or SNRIs are effective for pain management. They should only be prescribed by a specialist because it is uncertain if potential benefits outweigh potential harms.

Epidemiological data suggest that gabapentinoids (in particular, pregabalin), TCAs and SNRIs can alter or worsen mood, and cause suicidal thoughts or behaviours, particularly in the first 10 days of therapy. The risk appears to be higher in younger people (ie people younger than 30 years) and, for gabapentinoids, people with substance misuse. Although the absolute risk of suicidality or self-harm is low, determine the appropriateness of the adjuvant on a case-by-case basis. If a gabapentinoid, TCA or SNRI is started, discuss the risks with the patient and advise them to report any mood changes, or suicidal thoughts or behaviours. Monitor the patient regularly throughout therapy, but especially 1 week after starting the drug or when the dosage is increased. If mood is persistently worse or suicidality occurs, strongly consider withdrawing the drug and seeking psychiatric advice.

Gabapentinoids modulate central sensitisation. They have the potential for misuse and dependence. In adults, pregabalin and gabapentin have similar efficacy, but in practice, the pharmacokinetic properties of each drug may alter drug preference. In children, gabapentin is preferred—evidence does not support the use of pregabalin due to higher rates of adverse effects compared to gabapentin.

TCAs and SNRIs appear to relieve neuropathic and nociplastic pain independently of their mood-altering effect. Inhibition of synaptic noradrenaline and serotonin reuptake strengthens descending pain modulation. Although amitriptyline is most commonly used, it can cause unacceptable adverse effects including sedation; see ../../Psychotropic/ptg/c_ptg8-c68-s1.html#ptg8-c68-s1__tptg8-c68-tbl2 for the relative frequency of adverse effects of antidepressants.

The appropriate dose regimen depends on whether the drug is used for acute or chronic pain:

• in acute neuropathic pain, doses are often titrated quickly to achieve faster analgesia and adverse effects are managed simultaneously
• in chronic pain, doses are slowly titrated to effect to improve tolerability and reduce the likelihood of drug discontinuation. Although the target doses for neuropathic and nociplastic pain are similar, slower dose titration is required for patients with nociplastic pain (eg fibromyalgia) because they often have an increased sensitivity to the drugs’ effects.