Neuropathic pain: first-line agents and AU prescribing rules

What neuropathic pain actually is

Neuropathic pain — formally defined by the International Association for the Study of Pain (IASP) as pain caused by a lesion or disease of the somatosensory nervous system — differs fundamentally from nociceptive pain, the ordinary signal of tissue damage or inflammation. In neuropathic pain, the nervous system itself is injured or dysfunctional, and the pain is generated by that dysfunction rather than by an ongoing peripheral threat.

Roughly 7–10% of Australian adults live with neuropathic pain. Common presentations in general practice include:

• Painful diabetic peripheral neuropathy (DPN) — affects approximately 25% of people living with diabetes; typically a distal symmetric burning, “stocking-glove” distribution; coexists with numbness and reduced vibration sense
• Post-herpetic neuralgia (PHN) — dermatome pain persisting more than three months after herpes zoster; allodynia (clothing touching skin is painful) is often the most distressing feature; Shingrix vaccination reduces the risk of zoster and PHN substantially
• Radicular pain — dermatomal distribution from disc, foraminal stenosis, or spinal canal stenosis; sciatica is the most common variant; the radicular component is often burning or electric, distinct from the local back/neck ache
• Post-surgical neuralgias — post-thoracotomy, post-mastectomy, phantom limb, post-inguinal hernia; underdiagnosed because the causative event is attributed to an obvious surgical wound rather than nerve injury
• Trigeminal neuralgia — paroxysmal lancinating facial pain in the V2/V3 distribution, triggered by light touch, chewing, or cold air; a specific entity with a specific first-line treatment (carbamazepine)
• Chemotherapy-induced peripheral neuropathy (CIPN) — taxanes (paclitaxel, docetaxel), platinum agents (oxaliplatin, carboplatin), vinca alkaloids; often persistent after chemotherapy ends

The clinical importance of recognising neuropathic pain is that standard analgesics (NSAIDs, paracetamol, codeine) do not address the underlying mechanism, and the evidence-based first-line agents — tricyclic antidepressants (TCAs), duloxetine, gabapentin, pregabalin — are not analgesics in the traditional sense.

A. Core clinical — the AU general-practice framework

Recognising a neuropathic component

The DN4 questionnaire (Bouhassira 2005) is the most widely validated bedside screening tool. It scores seven symptom items and three examination items; a score of four or more out of ten identifies neuropathic pain with sensitivity 83% and specificity 90% in validated studies.

Positive features (suggest neuropathic):

• Burning, electric shock-like, or lancinating pain
• Spontaneous paraesthesia (tingling, pins and needles, crawling sensation)
• Dysaesthesia (abnormal, unpleasant sensation)
• Allodynia — pain triggered by normally non-painful stimuli such as light touch, cool air, or clothing
• Hyperalgesia — exaggerated, prolonged pain response to a painful stimulus

Negative features (also support neuropathic, by reducing sensory function in the affected distribution):

• Numbness, reduced sensation, weakness in a dermatomal or nerve-territory pattern

History to take

• Character, distribution, duration, severity, temporal pattern
• Triggers, alleviating factors, functional impact (sleep, work, activity, relationships)
• Comorbidities — diabetes, herpes zoster history, surgery, trauma, autoimmune disease, malignancy, HIV
• Medications causing neuropathy — chemotherapy agents, isoniazid, metronidazole, nitrofurantoin, amiodarone; note statins cause peripheral neuropathy rarely
• Substance use — alcohol (alcoholic neuropathy), opioid use history
• Red flags requiring urgent assessment: saddle anaesthesia, urinary retention, faecal incontinence (cauda equina syndrome); rapidly progressive weakness; unexplained weight loss, night sweats

Examination

Conduct a systematic sensory examination in the affected and contralateral distribution:

• Light touch (cotton wool), pinprick (disposable neurotip), vibration (128 Hz tuning fork), temperature (cool metal)
• Test allodynia explicitly (lightly stroking skin — does it produce pain?)
• Motor power — MRC grading; reflexes (diminished in radiculopathy and polyneuropathy)
• Provocative tests — straight-leg raise, slump test, femoral stretch test for radicular pain; Tinel’s and Phalen’s for entrapment neuropathy

Investigations

• Bloods: HbA1c, B12, folate, TSH, UEC, LFT, FBC, ESR/CRP; consider protein electrophoresis for unexplained polyneuropathy; HIV and hepatitis serology if risk factors present
• Nerve conduction studies (NCS) and EMG — confirms peripheral neuropathy, radiculopathy, or mononeuropathy; indicated when diagnosis is uncertain or atypical; also useful for medico-legal documentation
• MRI spine — for radicular features; MRI brain — for central neuropathic pain, trigeminal neuralgia (to exclude MS, vascular compression, tumour)
• Skin biopsy (specialist) — for suspected small fibre neuropathy when NCS is normal despite typical symptoms

Treatment hierarchy

The Australian Pain Society and eTG — Neuropathic pain align with NICE NG193:

1. Identify and treat the underlying cause — optimise glycaemic control for DPN; administer antiviral within 72 hours of zoster rash onset (reduces PHN risk); decompress entrapment neuropathies; treat nutritional deficiencies
2. First-line pharmacotherapy — amitriptyline/nortriptyline OR duloxetine OR pregabalin OR gabapentin; choice guided by comorbidity, side-effect profile, PBS Authority access
3. Non-pharmacological approaches from the outset — these are not adjuncts; they are core treatment
4. Second-line — rotate or rationally combine first-line agents (e.g., TCA + gabapentinoid)
5. Third-line and specialist — opioids for severe refractory or palliative contexts only; specialist interventional procedures for selected cases

B. Evidence appraisal — what the trials show

The Finnerup et al. Lancet Neurology 2015 systematic review and meta-analysis — 229 trials, over 12,000 participants — is the benchmark evidence synthesis for neuropathic pain pharmacotherapy:

Agent	NNT for 50% pain relief	Notes
Amitriptyline/nortriptyline (TCA)	~3.6	Most affordable; PBS general schedule
Gabapentin	~6.3	PBS Authority Required
Duloxetine (SNRI)	~6.4	PBS Authority for diabetic neuropathy specifically
Pregabalin	~7.7	PBS Authority Required — restrictive criteria

Cochrane reviews for individual conditions confirm these findings: amitriptyline for PHN and DPN; duloxetine for DPN (NNT ~5.8); gabapentin for PHN.

Trigeminal neuralgia — a specific exception: Carbamazepine achieves approximately 70% response rates in trigeminal neuralgia, making it the clear, unambiguous first-line regardless of the general neuropathic hierarchy. Cochrane review of carbamazepine for TN supports this strongly; all other agents are second-line by comparison.

The opioid question: Faculty of Pain Medicine, ANZCA and RACGP position statements are explicit: opioids play a limited, third-line role in chronic non-cancer neuropathic pain. The evidence for long-term opioid benefit is modest; harms — tolerance, dependence, hormonal effects, respiratory depression, mortality — are substantial and accumulate over time. Strong opioids are appropriate in palliative contexts, in severe refractory pain under specialist co-management, and for cancer-related neuropathic pain.

Non-pharmacological therapies with RCT support:

• Pain neuroscience education (“Explain Pain”) — developed in Australia by Prof Lorimer Moseley (UniSA); RCT evidence for reducing pain catastrophising, fear-avoidance, and disability
• CBT and ACT for chronic pain — Cochrane reviews show moderate effect sizes for both pain intensity and functional outcomes; Better Access programme funds 10 psychology sessions/year
• Physiotherapy with graded exercise — improves function, reduces deconditioning, supports return to activity
• Transcutaneous electrical nerve stimulation (TENS) — safe, inexpensive, modest and inconsistent evidence for neuropathic pain; reasonable to trial for selected patients
• Multidisciplinary pain management programmes (PMPs) — combining education, psychological therapy, and exercise in group format; RCT and systematic review evidence for reducing disability; available through public hospital pain services in each state

C. PBS prescribing, SafeScript, and practical dispensing

PBS Authority rules structure which first-line agents are accessible and when:

Amitriptyline and nortriptyline — PBS general schedule, no Authority required; cheap; the most accessible starting point for most patients with peripheral neuropathic pain.

Duloxetine — PBS General schedule for major depressive disorder; PBS Authority Required (Streamlined) specifically for diabetic peripheral neuropathic pain; for other neuropathic pain indications (PHN, post-surgical neuralgia, radicular neuropathic pain), duloxetine is a private prescription, which limits access for cost-sensitive patients.

Gabapentin — PBS Authority Required (Streamlined or Written) for neuropathic pain; document the indication and prior agents attempted in the Authority application.

Pregabalin (Lyrica) — PBS Authority Required (Restricted Benefit Streamlined): the Authority criteria typically require documented failure of, or contraindication to, at least two agents from the first-line class (TCA, SNRI, or gabapentin). In practice, this means most patients need a genuine therapeutic trial of amitriptyline or duloxetine before PBS Authority for pregabalin is grantable. Authority is also available for specific indications (post-herpetic neuralgia, spinal cord injury-related pain) with slightly different criteria — check current PBS listings at pbs.gov.au before prescribing.

Carbamazepine — PBS General schedule for trigeminal neuralgia and epilepsy; low cost; note HLA-B*1502 testing is recommended before prescribing in patients of Asian ancestry given the materially elevated Stevens-Johnson syndrome risk.

Opioids — Schedule 8; PBS General or Authority for chronic non-cancer severe pain; state authority and RTPM check required for ongoing prescribing in all states.

Real-Time Prescription Monitoring (RTPM / SafeScript):

SafeScript (Victoria) mandates a clinical check before prescribing pregabalin, gabapentin, opioids, benzodiazepines, tramadol, and several other high-risk medications. Queensland (QScript), Tasmania, South Australia, Western Australia, and the ACT have equivalent mandatory systems. NSW SafeScript is phasing to mandatory status. The check is a legal requirement in most Australian jurisdictions — it cannot be deferred or delegated.

Practical prescribing tips:

• Start amitriptyline at 10 mg nocte; the most common reason for therapeutic failure with TCAs is under-titration — titrate to 25–75 mg over several weeks, reassessing at each step
• Duloxetine 30 mg daily for the first two weeks before escalating to 60 mg substantially reduces nausea and improves tolerability
• When applying for pregabalin Authority, document prior agents tried, the dose reached, the duration, and the reason for switching (adverse effect or inadequate response)
• Avoid combining tramadol with SSRIs, SNRIs, or TCAs — serotonin syndrome risk is a practical concern in neuropathic pain patients who may be on duloxetine or amitriptyline

D. Australian operations

MBS pathways for neuropathic pain management:

• Standard GP attendances — items 23, 36, 44; telehealth equivalents 91790/92029/92060
• GP Comprehensive Care Management Plan (GPCCMP) — items 965/967 (replaced legacy 721/723 from 1 July 2025 under CDM reform); neuropathic pain as a chronic condition qualifies; plan includes up to five sessions/year with allied health (physiotherapy, psychology, OT, dietitian — 10 sessions/year for ATSI patients)
• Mental Health Care Plan (MHCP) — items 2715/2717 (preparation), 2712 (review); 10 subsidised psychology sessions/year; eligible when anxiety, depression, or psychological distress accompanies chronic pain; specify CBT for chronic pain or ACT on the referral
• Telehealth specialist pain consultations — particularly valuable for patients in rural and remote areas; pain medicine specialists (FFPMANZCA) can be accessed via video consult in most states

Multidisciplinary pain services:

Public multidisciplinary pain management programmes are available through major hospital pain centres in each state (Royal North Shore Hospital Sydney, Royal Melbourne Hospital, Royal Brisbane and Women’s Hospital, Royal Adelaide Hospital, Royal Perth Hospital, and affiliates). Group-based programmes are the primary format. Referral waits vary by state and urgency. Painaustralia maintains a directory and national advocacy on equitable pain care access.

Interventional pain medicine:

Refer to a pain medicine specialist (FFPMANZCA) for:

• Spinal cord stimulation (for failed back surgery syndrome, complex regional pain syndrome — PROCESS trial evidence)
• Nerve blocks — diagnostic and therapeutic (intercostal, occipital, pudendal, sympathetic)
• Radiofrequency ablation
• Intrathecal analgesia pumps (cancer and severe non-cancer refractory pain)

MBS specialist referral items 105/106 apply.

E. Special populations

Diabetes and diabetic peripheral neuropathy: The most important disease-modifying step is glycaemic optimisation. Per RACGP diabetes management guidelines, HbA1c targets are individualised; tight glycaemic control slows DPN progression. Annual foot examination, monofilament testing, and podiatry referral are integral. Duloxetine carries PBS Authority for DPN specifically — the only indication with this advantage.

Older adults: TCAs carry higher risk in elderly patients — anticholinergic burden (constipation, urinary retention, dry mouth, cognitive impairment), sedation, falls, and QTc prolongation. Prefer nortriptyline over amitriptyline (fewer anticholinergic effects). Use lower starting doses (5–10 mg nocte) and titrate slowly. Gabapentinoids cause dizziness and falls — titrate carefully and warn patients explicitly.

Pregnancy: Most neuropathic agents are avoided in pregnancy. If pharmacotherapy is essential, amitriptyline (Category C) is the preferred TCA with specialist perinatal input. Pregabalin, gabapentin, and duloxetine are avoided where possible. Seek specialist perinatal pain medicine input for moderate-to-severe cases.

Renal impairment: Pregabalin and gabapentin are renally cleared — dose reduction is required when eGFR is below 60 mL/min/1.73 m². Neither should be prescribed without dose adjustment in significant renal impairment. Opioid metabolites also accumulate in renal impairment — use shorter-acting agents, reduce doses, and monitor closely. Per AMH, specific dose-adjustment tables are essential for both drug classes.

History of substance use disorder: Minimise or avoid pregabalin, gabapentin, and opioids in this group. Non-pharmacological approaches should be maximised. Duloxetine or low-dose TCA are preferred. If opioid prescribing cannot be avoided, co-management with addiction medicine or specialist pain medicine is strongly advisable, with written opioid treatment agreements and RTPM vigilance.

Cancer-related neuropathic pain (CIPN, tumour invasion, post-surgical): More permissive opioid prescribing is appropriate in the palliative context. Per eTG — Palliative care, specialist palliative medicine involvement is advisable for moderate-to-severe cancer-related neuropathic pain.

When to escalate

Escalate urgently when:

• Cauda equina features — saddle anaesthesia, urinary retention, faecal incontinence → emergency surgical assessment
• Rapidly progressive weakness or evolving neuropathy — urgent neurology (Guillain-Barré, vasculitic neuropathy, mononeuritis multiplex)
• Trigeminal neuralgia refractory to adequate carbamazepine trial — neurology referral; MRI brain is required before surgical discussion

Refer routinely when:

• Failure of two adequate first-line pharmacotherapy trials at therapeutic doses for adequate duration (4–8 weeks)
• Diagnostic uncertainty — atypical distribution, possible small fibre neuropathy, central versus peripheral mechanism unclear
• Complex opioid stewardship situation — initiation, dose escalation, or taper in high-risk patients
• Spinal cord stimulation, nerve block, or other interventional procedures are under consideration
• Severe psychological comorbidity (major depressive disorder, PTSD, suicidality) accompanying chronic pain — requires coordinated mental health and pain management

What this article is and is not

This is general health information drawn from current Australian general practice evidence — eTG complete, RACGP, AMH, NPS MedicineWise, Australian Pain Society, Faculty of Pain Medicine ANZCA, and major trial sources. It is not personal medical advice and does not create a doctor–patient relationship. Drug doses, PBS Authority criteria, and RTPM requirements change — verify at pbs.gov.au and your state’s RTPM portal before prescribing.

For consumer-friendly information: HealthDirect — Neuropathic pain, Painaustralia, Better Health Channel.

For acute mental health crisis accompanying chronic pain: Lifeline 13 11 14, Beyond Blue 1300 22 4636.

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Sources cited

1. eTG complete — Neuropathic pain
2. RACGP — Chronic and persistent pain
3. Australian Medicines Handbook (AMH)
4. NPS MedicineWise
5. Australian Pain Society
6. Faculty of Pain Medicine, ANZCA
7. Painaustralia — National Strategic Action Plan for Pain Management
8. NICE NG193 — Neuropathic pain in adults
9. Finnerup NB et al — Pharmacotherapy for neuropathic pain in adults (Lancet Neurology 2015)
10. Bouhassira D et al — DN4 questionnaire validation (Pain 2005)
11. Cochrane — Pain, Palliative and Supportive Care group
12. IASP — Neuropathic pain definitions and classification
13. PBS — pregabalin, gabapentin, duloxetine, amitriptyline
14. SafeScript Victoria
15. HealthDirect — Neuropathic pain
16. Better Health Channel — Nerve pain