Prescribing drugs of dependence in general practice

Part C2 - The role of opioids in pain management - Chapter 5

Brief overview of adjuvants

Last revised: 02 Jun 2020

In this guide, ‘adjuvants’ refers to medications that are co-administered with analgesics to either enhance pain relief or manage adverse effects of the pain medication.

Respecting the caveats of placebo effects in pain, and the known problems of pain trials, the following is a review of the available evidence of pharmacological analgesic adjuvants.

Caffeine has been added to common analgesics such as paracetamol, ibuprofen and aspirin in the belief that it enhances analgesic efficacy.252 A small but statistically significant benefit has been shown when 100–130 mg dose of caffeine (equivalent to a mug of coffee) is added to these common analgesics. The effect appears to be independent to the pain condition or type of analgesic.252 With no serious adverse events reported, it is unlikely that adding caffeine to an analgesic will be harmful if the recommended dose is not exceeded.252

There is considerable variation in the comparative types and effectiveness of antidepressants on specific conditions. These variations are detailed under specific conditions.

All classes of antidepressants are associated with withdrawal syndromes253–256 and should be tapered slowly if the drug is discontinued. Antidepressant abuse and misuse have also been reported, but are rare. Most reported cases of antidepressant abuse occur in individuals with comorbid substance use and mood disorders.

Tricyclic antidepressants

Musculoskeletal pain

There is no significant difference between tricyclic antidepressants (TCAs) and placebo in pain relief for patients with chronic low back pain.257,258

Neuropathic pain

While TCAs are considered first-line and second-line therapies in neuropathic pain treatment,96,167,259–262 guideline recommendations differ and supportive data are of varied quality. Older analyses and guidelines, and those before the definition of neuropathic pain changed in 2011, appear more supportive.

More recent analyses report very modest efficacy compared to other antidepressants and anticonvulsants263 and suggest that the evidence base for TCAs in neuropathic pain is weak, due to the small magnitude of clinically meaningful effects and the high risk of bias in the RCTs.100,247,248,264,265 Large placebo responses, inadequate diagnostic criteria and poor phenotypic profiling probably account for modest trial outcomes.96

Neuropathic pain associated with cancer or human immunodeficiency virus (HIV) appears refractory to TCAs.

There is also support for some analgesic combinations in selected neuropathic pain conditions.94


In fibromyalgia, the most effective TCA appears to be amitriptyline (number needed to treat [NNT] 4.9).249,266

In practice

Amitriptyline probably provides very good pain relief to some patients with neuropathic pain or fibromyalgia, but in a minority; amitriptyline will not work for most people. When initiating a therapeutic trial, start at the lowest recommended dose (eg amitriptyline 5–10 mg at night) and assess the patient for benefit and harm at one week.100 If needed, increase the dose slowly to minimise adverse effects; the maximum dose is approximately 75–100 mg at night.

In older patients, TCAs should be used with caution. Medications with anticholinergic activity increases risk of cognitive impairment, risk of falls and even mortality.267,268

Serotonin noradrenaline reuptake inhibitors

Musculoskeletal pain

Duloxetine is a recommended treatment in updated guidelines for osteoarthritis.269 It is as effective as other first-line treatments (eg NSAIDs) for pain and disability of osteoarthritis.270,271 Duloxetine appears to be well tolerated in older patients with osteoarthritis pain (of the knee).270

Neuropathic pain

There is evidence that some antidepressants, in particular duloxetine and venlafaxine, may be effective first-line treatments for neuropathic pain, including diabetic polyneuropathy.96,255,256,263 Duloxetine has been shown to be effective and safe for the treatment of painful diabetic peripheral neuropathy in older patients.272

Chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood and is resistant to treatment. However, duloxetine (30 mg titrated to 60 mg/day over five weeks) has resulted in a modest reduction in pain severity relative to placebo.273 Additional benefits included reduced numbness and tingling of the feet, and improved quality of life.273


The serotonin noradrenaline reuptake inhibitor (SNRI) duloxetine is effective in reducing pain and improving quality of life in fibromyalgia.249,274 The NNT is approximately six.256,275 However, it is not effective at improving sleep or fatigue.274

In practice

SNRIs are regarded as a first-line therapy for managing neuropathic pain.96 The NNT is approximately seven for 50% pain relief.96 When initiating a therapeutic trial, start at the lowest recommended dose (eg duloxetine 30 mg) and assess the patient for benefit and harm at one week. If insufficient but partial pain relief is achieved, increase the dose and reassess within one week; this may be repeated. Modest reduction in pain severity may be achieved with duloxetine dose titrated to 60 mg/day over five weeks. Duloxetine 60–120 mg/day provides analgesia for diabetic neuropathy, with lower efficacy for fibromyalgia.

Use the lowest individualised effective dose to minimise adverse effects, the most common of which is intolerable drowsiness. If the benefit–harm ratio is unacceptable, consider stopping the drug.

Selective serotonin reuptake inhibitors

There is only limited evidence for the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in neuropathic pain.262

Alpha-2-delta ligands (gabapentin and pregabalin)

Gabapentin and pregabalin are commonly used in pain management. Initially classified as membrane stabilisers, recent evidence indicates they are more correctly classified as anticonvulsants.

Neuropathic pain

Gabapentin and pregabalin are recommended for use in neuropathic pain and are proposed as first-line treatments.96 In general practice settings, evidence to support the use of gabapentinoids in treatment of neuropathic pain is varied.

Some analyses found significant benefit with use of gabapentin and pregabalin in chronic neuropathic pain (eg diabetic polyneuropathy, post-herpetic neuralgia, central neuropathic pain)276–279 and neuropathic pain caused by traumatic or post-surgical nerve injury.280 However, other analyses suggest that only a minority of people achieved acceptably good pain relief with either drug, benefits of treatment came with a high risk of adverse events,276 and that the evidence base is weak due to the small magnitude of clinically meaningful effects and the high risk of bias in the RCTs.


Gabapentin and pregabalin have shown effectiveness in relieving fibromyalgia pain.276,281

In practice

Anticonvulsant agents are regarded as one of the main first-line approaches toward management of chronic neuropathic pain. The NNT ranges from four to 10 for the important outcome of reduction of pain intensity by 50% or more.96,276 Some studies suggest the NNT is greater than 10.100

When initiating a therapeutic trial, start at the lowest recommended dose (eg pregabalin 25 mg at night or twice daily) and assess the patient for benefit and harm at one week.100 If insufficient but partial pain relief is achieved, increase the dose (eg pregabalin can be increased by 25–75 mg per day on a weekly basis) and reassess within one week.100 Success is either achieved or not within the first two weeks or so of treatment; it tends to last when achieved.98,99,221 If functionally meaningful benefit is absent during reassessment, stop the drug and try alternative approaches.100 The most common side effect is intolerable drowsiness.

The dependence, abuse and misuse potential for gabapentinoids is increasingly being reported,282 but appears to be limited to susceptible populations (eg recreational drug users).283 Physicians considering prescribing gabapentinoids for pain should carefully evaluate for a possible previous history of SUDs, while being able to promptly identify signs of problematic use of pregabalin or gabapentin and provide possible assistance in tapering off the medication.284

Other anticonvulsants

Carbamazepine is the first-line agent for trigeminal neuralgia as it is supported by good evidence; however, the evidence for other chronic neuropathic pain is less strong.268 Valproate may reduce pain in diabetic polyneuropathy based on very small RCTs of poor quality285 but otherwise lacks evidence support.

Lamotrigine has shown no analgesic benefit in neuropathic pain in large, high-quality, long-duration RCTs.276

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