Neuropathic Pain

Neuropathic pain is pain caused directly by a lesion or disease affecting the somatosensory nervous system, rather than by ongoing tissue injury or inflammation — a fundamentally different mechanism from the nociceptive pain covered in the Acute Pain chapter, and one that acetaminophen and NSAIDs do not reliably treat. It can arise from damage anywhere along the somatosensory pathway: peripheral nerves (diabetic peripheral neuropathy, postherpetic neuralgia, nerve trauma), nerve roots (cervical or lumbar radiculopathy), or the central nervous system itself (pain after stroke or spinal cord injury, multiple sclerosis). Because it responds to a different set of drugs — gabapentinoids, certain antidepressants, and topical agents rather than conventional analgesics — correctly recognizing neuropathic pain, ideally supported by a validated screening tool such as the DN4, is the step that determines everything that follows.

Trigeminal neuralgia and acute nerve root compression are managed differently again: trigeminal neuralgia responds specifically to carbamazepine rather than the usual first-line agents, and acute nerve root pain is treated acutely like other acute pain before neuropathic-specific therapy is considered. This chapter also carries a deliberate opioid-sparing message — opioids, including tramadol, are third-line, reserved for a carefully monitored trial only after adequate first- and second-line therapy has been tried.^[1]

How neuropathic pain typically presents

Pain quality often differs qualitatively from nociceptive pain: spontaneous ongoing pain described as burning or aching, paroxysmal pain described as shooting or electric shock-like, and evoked pain triggered by a stimulus that would not normally be painful. Numbness or reduced sensation frequently coexists with the pain itself in the same distribution — a patient may describe an area as simultaneously numb and painful.

Sensory findings on examination

Complex regional pain syndrome (CRPS) type I — historically called reflex sympathetic dystrophy — is a distinct neuropathic pain presentation with neurovascular and dystrophic features: burning pain in a nonanatomical distribution, allodynia, sweating, and skin colour/temperature change, progressing if untreated to glossy skin, altered hair/nail growth, osteoporosis, and contractures. CRPS type II (causalgia) follows a clear nerve injury and is managed the same way as other chronic peripheral neuropathic pain.

• Diabetes mellitus, particularly with longstanding or poorly controlled hyperglycemia (diabetic peripheral neuropathy).
• Age over 50 combined with reduced immune competence — the main risk factors for herpes zoster reactivation and subsequent postherpetic neuralgia.
• Nerve trauma, including surgical incision, amputation (phantom limb pain), or a penetrating/crush injury.
• Chemotherapy exposure, particularly with platinum agents, taxanes, or vinca alkaloids.
• HIV infection.
• Degenerative spine disease with disc herniation or nerve root compression, most often at C5-C6 or L5-S1.
• Stroke or spinal cord injury (central neuropathic pain).
• Multiple sclerosis.
• Malignancy directly invading or compressing a nerve.
• A personal or family history of chemical dependency, or a history of severe psychiatric disorder — relevant to weighing the risk of opioid therapy if that stage is reached, not itself a cause of neuropathic pain.

Distinguishing neuropathic from nociceptive pain

Many patients have mixed pain — for example, chronic low back pain with a radicular neuropathic component plus mechanical nociceptive pain. Treat each component according to its own mechanism rather than assuming one therapy will cover both.

History

• Characterize the pain's temporal profile (constant vs. paroxysmal), quality (burning, shooting, electric shock-like, tingling), and distribution (whether it follows a nerve, root, or dermatomal pattern).
• Ask specifically about features suggesting an underlying treatable cause requiring separate workup: new malignant, ischemic, inflammatory, or infectious disease.
• Assess functional status, mood, sleep, and quality of life with a validated tool (e.g., Brief Pain Inventory, Hospital Anxiety and Depression Scale) — these guide both the treatment plan and the definition of a successful response.
• Review current and previous treatments in detail, including the actual dose and duration tried — many reported "failures" reflect an inadequate trial rather than true non-response.
• Ask about a personal or family history of substance use disorder and any history of severe psychiatric illness, particularly before considering opioid therapy.
• Apply a validated neuropathic pain screening tool (DN4 or painDETECT, below) when the diagnosis is uncertain.

Physical examination

• Map the area of sensory abnormality — hypoesthesia, allodynia, hyperalgesia, hyperesthesia, dysesthesia, or hyperpathia — and confirm it corresponds to a plausible nerve, root, or central distribution.
• Perform a focused neurologic exam for motor weakness, reflex changes, or other findings suggesting a progressive lesion needing imaging and possible surgical referral (see Red Flags & Refer).
• Look for a concurrent musculoskeletal or psychological contributor to the pain presentation — mixed pain is common, and each component needs its own treatment approach.

Investigations

• MRI or CT imaging when a space-occupying or compressive lesion is suspected (progressive neurologic deficit, malignancy risk, or failure of conservative management for nerve root pain) — not needed routinely for typical diabetic peripheral neuropathy or postherpetic neuralgia with a classic history and exam.
• Electromyography/nerve conduction studies when the diagnosis or the specific nerve(s) involved is unclear.
• Diagnostic sympathetic blockade when complex regional pain syndrome is suspected and the diagnosis is in question.

Neuropathic pain screening questionnaires

The DN4 (Douleur Neuropathique 4) is a 10-item screening tool combining 7 patient-reported items with 3 brief clinician-administered sensory-examination items — 1 point for each item present, out of a maximum of 10.^[4] It is a simple, unambiguous point-sum, structurally similar to other validated scoring tools used elsewhere in this platform, though it still requires a brief hands-on sensory exam rather than being purely self-reported.

A total score of 4 or more out of 10 supports a neuropathic pain component. Use the DN4 to decide whether a neuropathic-specific agent is appropriate — it does not replace clinical judgement or the search for an underlying cause.

painDETECT is an alternative, entirely patient-completed screening questionnaire that needs no hands-on sensory examination, making it useful when a bedside exam is not practical.^[5] A score of 19 or higher suggests a neuropathic component is likely, 13-18 is ambiguous, and 12 or below suggests it is unlikely.

• Reduce pain from moderate-or-severe to mild — complete resolution is uncommon and should not be the stated goal for most patients.
• Balance meaningful pain relief against tolerable, manageable side effects; the right dose is not always the maximum tolerated dose.
• Restore function: sleep, mood, activities of daily living, and work/social participation, not just the pain score in isolation.
• Minimize opioid exposure — reserve opioids for a monitored, time-limited trial only after non-opioid first- and second-line options have had an adequate trial.
• Identify and treat any reversible underlying contributor found on assessment (for example, optimizing glycemic control in diabetic peripheral neuropathy, or addressing a compressive lesion) alongside symptomatic pain therapy.
• Engage the patient as an active participant in a multimodal plan that combines pharmacotherapy with the nonpharmacologic measures below, rather than relying on medication alone.

• Physiotherapy, supervised exercise, and physical reconditioning — evidence is limited for many modalities, but they are reasonable adjuncts and should be combined with pharmacotherapy rather than used as an alternative to it.
• Cognitive behavioural therapy, mindfulness-based approaches, and other psychotherapy — support coping and function, and address the anxiety/depression that commonly accompanies chronic neuropathic pain.
• Sleep hygiene counselling and, where relevant, treatment of comorbid insomnia — poor sleep both worsens pain perception and is worsened by it.
• Set expectations explicitly at the first visit: the realistic goal is reducing pain from moderate-or-severe to mild, not complete resolution. Most patients achieve partial relief, and a minority achieve near-complete relief. Framing partial response as a genuine treatment success — rather than a failure requiring escalation — reduces unnecessary dose-chasing and inappropriate opioid escalation.
• Schedule regular follow-up visits even when a specific new intervention is not planned — ongoing contact provides psychological support and allows early detection of both inadequate response and emerging adverse effects.
• For diabetic peripheral neuropathy, reinforce glycemic control as part of the overall plan, alongside pain-specific therapy.
• For nerve root compression that fails conservative management, or for trigeminal neuralgia refractory to medical therapy, surgical options exist (nerve decompression, microvascular decompression, ablative procedures) — see Choose Initial Treatment and Treatment Failure & Next Step.
• Interventional procedures such as epidural steroid injections and sympathetic blocks are offered by some chronic pain clinics, but current evidence supporting their efficacy specifically for neuropathic pain is limited — they are not a substitute for an adequate pharmacologic trial.

Pregnancy

Use nonpharmacologic measures preferentially and avoid drug therapy for neuropathic pain in pregnancy whenever possible; if treatment is genuinely needed, weigh the risks and benefits of the specific agent.

Preferred if a drug is needed amitriptyline — TCAs have the most reassuring pregnancy safety data among the agents used for neuropathic pain.

Alternative SNRIs (venlafaxine, duloxetine) are not associated with an increased major-malformation risk but are generally less effective for neuropathic pain than TCAs; venlafaxine exposure late in pregnancy has been associated with transient neonatal neurobehavioural symptoms (agitation, jitteriness, feeding difficulty).

Topical lidocaine is not expected to result in meaningful systemic absorption and is considered safe in pregnancy.

Avoid gabapentin and pregabalin — pregnancy safety data are insufficient to support routine use; avoid unless no other option is appropriate and specialist input supports the decision.

Avoid valproic acid/divalproex sodium — increased neural tube defect risk.

Carbamazepine and oxcarbazepine are associated with an increased risk of major and minor malformations, including neural tube defects. If either is genuinely required (for example, trigeminal neuralgia unresponsive to alternatives), start high-dose folic acid supplementation (1 mg daily) at least 3 months before a planned conception, continuing through 12 weeks' gestation, then continue a standard prenatal multivitamin (0.4-1 mg folic acid) through pregnancy and for 4-6 weeks postpartum or while breastfeeding continues.

Opioid use in the first trimester carries a small absolute increase in congenital heart defect and neural tube defect risk; near-term use can cause neonatal respiratory depression, sedation, and withdrawal. Tramadol use has also been associated with neonatal withdrawal after prolonged maternal use. Reserve opioids in pregnancy for situations where the benefit clearly outweighs these risks, with specialist input.

Breastfeeding

TCAs are not expected to cause adverse effects in the breastfed infant. With SNRIs, monitor the breastfed infant for drowsiness and adequate weight gain/developmental progress. Topical lidocaine is not expected to cause infant adverse effects — keep infant skin away from treated areas. Gabapentin transfers into breast milk at low levels — monitor for infant drowsiness and adequate weight gain; avoid pregabalin while breastfeeding given insufficient safety data. Carbamazepine and oxcarbazepine are considered compatible with breastfeeding. Monitor infants exposed to opioids or tramadol via breast milk for sedation, poor feeding, or respiratory depression.

Older adults / frail elderly

Start at the lowest available dose and titrate more slowly than in younger adults, aiming for the lowest effective dose rather than the usual adult target. Actively minimize the total number of CNS-active drugs (antidepressants, gabapentinoids, opioids, benzodiazepines) in patients with a history of falls or fractures — each of these classes independently increases fall risk in this population.^[10][11]

Renal impairment

Gabapentin and pregabalin both require dose reduction based on creatinine clearance (see Drug Tables) — this is the single most common dosing error with these agents in renal impairment. Duloxetine is contraindicated if ClCr is under 30 mL/min. Venlafaxine requires dose reduction if ClCr is under 70 mL/min. Tramadol requires dose reduction if ClCr is under 30 mL/min. TCAs and topical lidocaine/capsaicin do not require renal dose adjustment.

Hepatic impairment

Avoid duloxetine in significant hepatic impairment. TCAs and opioids may need dose reduction and slower titration given hepatic metabolism — use lower starting doses and monitor closely.

Arrange initial follow-up around 2 weeks after starting or adjusting therapy, then at regular intervals thereafter — sooner if a new drug or dose change carries a specific early risk to monitor (for example, sodium or cardiac conduction).

• Track pain intensity with a simple 0-10 numeric rating scale, at rest and with activity, comparing to the pre-treatment baseline at every visit.
• Assess function (e.g., Brief Pain Inventory or Pain Disability Index), mood (e.g., Hospital Anxiety and Depression Scale), sleep, and adherence at follow-up — pain relief without functional improvement is an incomplete response.
• Check serum sodium at baseline and with dose changes for any antiepileptic or SNRI, given the shared SIADH/hyponatremia risk.
• Reassess renal function periodically in patients on gabapentin, pregabalin, duloxetine, venlafaxine, or tramadol, and adjust doses as renal function changes.
• Obtain or repeat an ECG when starting or increasing a TCA in anyone with cardiac risk factors.
• For carbamazepine specifically: CBC, electrolytes, and liver enzymes roughly every 1-2 weeks for the first 3 months, then periodically, given the risk of blood dyscrasia and hepatotoxicity in the early treatment period.
• If an opioid is used at any line of therapy, apply the same monitoring as any chronic non-cancer pain opioid trial — regular visits (monthly or more often initially), a documented treatment agreement, functional and mood assessment at every visit, and screening for misuse behaviour.^[8]
• After 1-3 months of stable relief, consider a supervised trial of dose reduction — postherpetic neuralgia in particular can remit spontaneously, and trigeminal neuralgia can enter remission — tapering gradually to avoid withdrawal/rebound symptoms.

1. Confirm the trial was actually adequate: the correct dose was reached (or the maximum tolerated dose, if lower) for at least 2-3 months, with real adherence — a "failed" trial that was underdosed or too short is not a true failure.
2. Re-confirm the diagnosis: re-screen with DN4/painDETECT, reconsider whether an undiagnosed reversible cause (for example, a compressive lesion or an uncontrolled metabolic cause) is driving the pain, and re-examine for a nociceptive or mixed-pain component that would need a different approach.
3. For partial response to first-line monotherapy: add a second first-line agent from a different class (for example, a gabapentinoid plus a TCA or SNRI) rather than repeatedly increasing the same drug beyond its tolerated dose.
4. For no response to an adequate first-line trial: switch to a different first-line class rather than trying a second agent from the same class.
5. For localized pain that persists despite an adequate systemic trial: add topical lidocaine or capsaicin over the specific painful area.
6. For pain that remains significant despite adequate first- and second-line trials, alone and in combination: refer for specialist input on third-line options — tramadol or another opioid as a monitored trial, or botulinum toxin A injections for refractory focal peripheral neuropathic pain.
7. For trigeminal neuralgia failing carbamazepine: switch to oxcarbazepine, or reduce the carbamazepine dose to a tolerable level and add baclofen; if medical therapy remains inadequate, refer for neurosurgical evaluation.
8. Throughout, actively distinguish between "the drug isn't working" and "the drug isn't tolerated" — an intolerable side effect at an inadequate dose calls for a different agent, not abandoning pharmacotherapy altogether.

• Using acetaminophen or an NSAID as primary therapy for neuropathic pain — evidence does not support their use as an effective standalone treatment, with the exception of the acute phase of nerve root compression, where they are appropriate.
• Combining a TCA with an SNRI, given the added serotonergic and cardiac risk with no established additional benefit.^[2]
• Declaring a first-line agent a failure before reaching an adequate dose or an adequate 2-3 month trial duration.
• Starting tramadol or another opioid as a first- or second-line agent instead of reserving it for after adequate first- and second-line trials.
• Missing the additive respiratory depression risk when a gabapentinoid is combined with an opioid — counsel on this specifically and use the lowest effective combined doses.^[3]
• Forgetting renal dose adjustment for gabapentin, pregabalin, duloxetine (contraindicated below ClCr 30 mL/min), venlafaxine, or tramadol.
• Starting a TCA in an older adult or a patient with cardiac disease without checking for contraindications or obtaining an ECG first.
• Using codeine, or tramadol, in a child under 12 years of age.
• Not setting realistic expectations up front — patients and prescribers who expect complete pain resolution often see a genuinely successful partial response as a failure, leading to unnecessary drug-switching or dose escalation.
• Treating trigeminal neuralgia with the standard first-line neuropathic pain agents instead of carbamazepine or oxcarbazepine — it responds poorly to the usual first-line drugs.
• Missing a red flag (progressive neurologic deficit, cauda equina signs, features suggesting malignancy) and treating symptomatically instead of investigating and referring.
• Using cannabinoids as a routine, general-purpose neuropathic pain therapy rather than reserving them for their specific approved indication under specialist direction.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Gabapentinoids (1st line)

Tricyclic antidepressants (1st line)

All TCAs: metabolized by cytochrome P450, with potential interactions with other CYP substrates/inhibitors (e.g., erythromycin, fluoxetine, fluvoxamine, paroxetine) or inducers (e.g., carbamazepine, phenytoin, rifampin); increased sedation with other CNS depressants such as alcohol; increased anticholinergic burden with other anticholinergic agents. Avoid in patients with prostatic hypertrophy, angle-closure glaucoma, or significant heart disease because of cardiac conduction/arrhythmia risk.

SNRIs (1st line)

Topical agents (2nd line, localized peripheral neuropathic pain)

Antiepileptics for trigeminal neuralgia and refractory adjunctive use

Carbamazepine and oxcarbazepine are 1st/2nd line specifically for trigeminal neuralgia. Clonazepam, valproic acid/divalproex sodium, lamotrigine, and topiramate are reserved for refractory cases, as an adjunct, or when carbamazepine/oxcarbazepine cannot be used.

Opioids (3rd line, including tramadol)

Reserve for after an adequate trial of first- and second-line agents, applying standard chronic non-cancer pain opioid safeguards. Avoid meperidine (accumulation of the excitotoxic metabolite normeperidine can cause myoclonus and seizures). Codeine is a poor choice for moderate-severe pain of any kind given unreliable conversion to morphine across CYP2D6 metabolizer phenotypes, and codeine/tramadol are not recommended under age 12.

Botulinum toxin (3rd line, refractory focal peripheral neuropathic pain)

Cannabinoids (not routinely recommended)

Current evidence gives a weak recommendation against cannabinoids as general neuropathic pain therapy. Nabiximols retains a specific Health Canada-approved indication for multiple sclerosis-related neuropathic pain and spasticity and should be reserved for that context under specialist direction.

Antivirals for acute herpes zoster

Most effective when started within 72 hours of rash onset; also reasonable in a patient over 60 with new severe unilateral neuropathic pain in a dermatomal distribution even before a rash appears, since these agents are safe and well tolerated. Reduces the severity of the acute rash/pain; evidence that antivirals reliably prevent postherpetic neuralgia is limited.

Evidence note: drug inventory, dosing, adverse effects, and comments reflect standard Canadian practice, cross-checked against current NeuPSIG, Diabetes Canada, CanPain SCI, and European Academy of Neurology guidance.^[12]