Neuropathic and Nociplastic Pain Pharmacotherapy

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The pain "set point" or "volume control" of an individual is determined partially by the levels of neurotransmitters on the left that amplify pain signals and those on the right that dampen pain signals. Therefore, an increase in neurotransmitters on the left or a decrease in those on the right may result in diffuse hyperalgesia, which is a common symptom of chronic pain conditions. The chart displays the levels of these neurotransmitters in the cerebrospinal fluid of fibromyalgia (FM) patients, with the arrows indicating the direction of abnormality. The opioidergic system is the "odd one out" being increased. Modified from Hochberg. Note: Nerve Growth Factor inhibitors (monoclonal antibodies) were found to be effective but had a risk of rapidly progressive osteoarthritis.

Central sensitisation is an amplification of pain signaling within the central nervous system (CNS), leading to hypersensitivity (e.g. allodynia, hyperalgesia) out of proportion to any tissue injury. It underpins nociplastic and many neuropathic pain syndromes – such as fibromyalgia, complex regional pain syndrome (CRPS), diabetic neuropathy, and post-herpetic neuralgia. It may be primary (no ongoing peripheral driver) or secondary (out of proportion to an ongoing peripheral driver).

Patients with demonstrable signs of central sensitisation (e.g. enhanced temporal summation, reduced conditioned pain modulation) often respond poorly to standard analgesics. This guideline is an attempt at synthesising the evidence for different individual treatments into a more personalised and cohesive whole. i.e. choosing medication based on sensitisation profiles and looking at combination treatments for difficult to treat pain.

This guideline is modeled on hypertension and heart failure management, where multiple agents targeting different pathways are used concurrently. In hypertension most patients need two or three medications targeting different aspects of the disease. In heart failure the standard of care is to be on four different agents (ACEi, B-blocker, spironolactone, and SGLT2i).

Scope

This guideline focuses on pharmacologic management of chronic pain with clear features of central sensitisation in adults residing in New Zealand. The rationale for medication is direct modulation of central sensitisation mechanisms, using both on-label therapies and mechanistically sound off-label options. There are unique challenges with treating chronic pain in New Zealand (for example the unavailability of some medications) and so a local guideline is needed.

Goal: The target pain relief is 30-50%, as achieving anything more than 50% relief is not realistic currently in most cases.

The guideline does not cover:

• Pure nociceptive chronic pain. The notion that all chronic pain is purely due to sensitisation is manifestly false and not evidence based.
• Psychosocial interventions.
• Named conditions causing local pain (e.g. trigeminal neuralgia, migraine, CRPS, etc). Guidelines specific to those conditions should be followed instead. Heterogenous nociplastic conditions like Fibromyalgia are within the remit of this guideline.
• Addressing peripheral drivers in secondary central sensitisation.
• Selecting medications purely for comorbid conditions (e.g. depression, insomnia) rather than pain itself. Psychological distress is recognised to be an expected outcome of difficult to control pain.
• Chronic inflammation. Inflammation can cause local allodynia (e.g. vertebral endplate oedema, de Quervains, etc).

Pathophysiology of Central Sensitisation in Pain

Central sensitisation involves multiple maladaptive neurophysiological changes:

• Excessive Excitatory Neurotransmission: Repeated or intense nociceptive input causes increased synaptic efficacy in spinal dorsal horn neurons (wind-up) mainly via glutamate and N-methyl-D-aspartate (NMDA) receptor activation. This leads to lowered pain thresholds, expansion of receptive fields, and persistent pain after stimuli. Key features include temporal summation of pain and aftersensations (hyperpathia)
• Reduced Inhibitory Modulation: Endogenous pain-inhibitory pathways (descending noradrenergic/serotonergic tracts from the brainstem) become deficient. Loss of inhibitory neurotransmitters (GABA, glycine) and impaired descending control contributes to pain amplification. Patients with central sensitisation often have impaired conditioned pain modulation (a proxy for deficient descending inhibition). Enhancing these pathways can help normalize pain processing.
• Neuroimmune and Glial Activation: Chronic pain can activate spinal cord microglia and astrocytes, releasing pro-inflammatory cytokines and excitatory mediators that sustain central hypersensitivity. Neuroinflammation in the CNS is thought to play a role in fibromyalgia and other centrally sensitized states. Modulating glial activity (e.g. via certain immunomodulatory agents) may therefore reduce central sensitisation.
• Sympathetic Facilitation: In some neuropathic conditions (e.g. CRPS), sympathetic nervous system activity can exacerbate central pain through α-adrenergic receptors coupling with nociceptive pathways (sympathetically maintained pain). This provides a rationale for adrenergic modulators in select cases.

Understanding these pathways informs a multitarget treatment strategy: each class of drug can address a different aberrant mechanism. No single agent is likely to fully reverse established central sensitisation; hence combining drugs (at lower doses of each) is advocated to maximize analgesia while minimizing side effects. This strategy mirrors other chronic disorders (e.g. combining an ACE inhibitor + β-blocker + spironolactone + SGLT2 inhibitor in heart failure) to tackle complex pathophysiology.

Pharmacological Treatment Classes

1. Monoaminergic Antidepressants (Enhancers of Descending Inhibition)

Mechanism: These drugs increase synaptic serotonin and/or norepinephrine in descending pain-modulating pathways, thereby boosting inhibitory signals in the spinal cord. By restoring the balance between inhibition and excitation, they help “dial down” centrally amplified pain. They also modulate neurotransmitters in the dorsal horn, indirectly reducing wind-up.

Drug Classes & Examples:

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Duloxetine, Milnacipran, Venlafaxine. Duloxetine and milnacipran are FDA-approved for fibromyalgia (a prototypical central sensitisation syndrome) but are not available in New Zealand. Duloxetine is effective in diabetic neuropathy and other neuropathic pain conditions. These (except venlafaxine) have robust evidence for pain reduction (Level A evidence: multiple RCTs) and are considered first-line agents. SNRIs improve pain by increasing spinal NE/5-HT which enhances descending inhibition. They often also alleviate comorbid fatigue and mood symptoms, but here they are chosen for direct analgesia. In countries where duloxetine is available, clinicians start at low dose (e.g. duloxetine 30 mg daily) and titrate to effect (typical 60 mg daily for pain). Unfortunately of the SNRIs only Venlafaxine is available in New Zealand. This agent does not have the any good clinical evidence for chronic pain. The receptor binding also isn't comparable to the other SNRIs as high doses are needed to obtain NET receptors blockade. Hence in New Zealand SNRIs should not be first line.
• Tricyclic Antidepressants (TCAs): Amitriptyline, Nortriptyline, Desipramine. TCAs were among the first effective treatments for neuropathic pain and remain a first-line option (Level A evidence). They inhibit NE and 5-HT reuptake (like SNRIs) and additionally block NMDA receptors and sodium channels at higher doses, providing multimodal analgesia. Amitriptyline ~25–75 mg at night often reduces neuropathic pain and fibromyalgia pain. TCAs’ sedative effect can improve sleep in fibromyalgia and other central pain (useful if insomnia is present. Due to side effects (anticholinergic effects, sedation), nortriptyline or desipramine are sometimes better tolerated (less sedation) for older patients. Desipramine isnt available in New Zealand. TCAs are first-line, especially in patients with concomitant poor sleep, but use caution in those with cardiac risk due to arrhythmogenic potential. If the patient is already on an SSRI then low dose nortriptyline is preferred because at low doses there will generally be limited SERT blockade.

Role in Therapy: First-line foundation. SNRIs or TCAs can be used as cornerstone medications in central sensitisation pain (TCAs only in NZ). If duloxetine becomes available in the future then choose based on patient comorbidities and tolerability (e.g. duloxetine for a patient with daytime fatigue or depression; amitriptyline for an patient with insomnia but avoid if severe dry mouth or cardiac issues). Combining an SNRI with a TCA is not recommended (no added benefit but higher risk. However, one antidepressant can be combined with non-antidepressant classes (see combinations below). If monotherapy with one agent is suboptimal, adding a low-dose second agent from a different class (e.g. TCA + gabapentinoid) is preferable to maximizing one drug to high dose.

Evidence: High-quality trials support SNRIs (duloxetine, milnacipran) and TCAs in fibromyalgia and neuropathic pain. For example, duloxetine 60 mg daily significantly reduces pain in diabetic neuropathy and fibromyalgia versus placebo (number-needed-to-treat ~5-6) in multiple RCTs. Amitriptyline has shown ≥30–50% pain reduction in classic trials of neuropathic pain (e.g. postherpetic neuralgia), though data in pure nociplastic pain are less extensive. Guidelines consistently list SNRIs and TCAs as first-line for centralized or neuropathic pain.

2. Calcium Channel α2δ Ligands (Modulators of Neuronal Excitability)

Mechanism: The gabapentinoid anticonvulsants bind the α2δ subunit of voltage-gated calcium channels on hyperexcited neurons (particularly in the dorsal horn and trigeminal nucleus). This reduces calcium influx and thus diminishes release of excitatory neurotransmitters (glutamate, substance P) involved in central sensitisation. The net effect is reduced neuronal hyperexcitability and dampening of abnormal pain transmission.

Examples: Gabapentin and Pregabalin. Both are well-established first-line medications for neuropathic pain (Level A evidence). Pregabalin has FDA approval for fibromyalgia and neuropathic pain conditions, indicating robust evidence of efficacy. Typical dosing: gabapentin is titrated from 300 mg up to 1200-2400 mg/day in divided doses; pregabalin from 50 mg up to ~300-450 mg/day in divided doses. Both require gradual titration to minimize sedation and dizziness.

Role in Therapy: First-line foundation, often combined with an antidepressant for synergistic effect. Clinical practice and trials support combining gabapentinoids with SNRIs or TCAs to improve pain relief when monotherapy is inadequate. The combination allows use of moderate doses of each: for example, one study found gabapentin (2400 mg) + nortriptyline (50 mg) outperformed either alone. Thus, gabapentinoids serve as a core agent to reduce central neuronal firing and should be part of initial multimodal regimens, particularly in patients with prominent allodynia or shooting neuropathic pain.

Evidence: Extensive evidence supports gabapentinoids. Pregabalin and gabapentin have multiple positive RCTs in diabetic neuropathy, postherpetic neuralgia, spinal cord injury pain, and fibromyalgia. They are recommended as first-line in numerous guidelines (e.g. EFNS, NeuPSIG). The number-needed-to-treat for ≥50% pain relief is around 7 for gabapentin and 8 for pregabalin in neuropathic pain meta-analyses. While not all patients achieve a good response, a significant subset get substantial relief. Common side effects are sedation, dizziness, and peripheral edema; these often limit dose, hence the benefit of combination (to avoid pushing to intolerable doses of one drug.

The distinct mechanism of gabapentinoids, primarily modulating presynaptic calcium channels , is complementary to agents that enhance postsynaptic inhibition via descending pathways (TCAs/SNRIs) or directly block postsynaptic receptors like NMDA. This provides a strong rationale for combining gabapentinoids with TCAs or SNRIs, a strategy frequently employed in clinical practice to target multiple facets of CS. The observation that gabapentin reduces experimental temporal summation suggests potential utility in patients exhibiting enhanced facilitation. This phenotype might overlap with the high TS profile responsive to ketamine , indicating shared underlying hyperexcitability mechanisms potentially amenable to different pharmacological approaches.

Despite the mechanistic rationale, large systematic reviews of combination therapy trials have often failed to demonstrate robust superiority of gabapentinoid-antidepressant combinations over both respective monotherapies in unselected populations. This again underscores the likely importance of patient heterogeneity and the need for better stratification. A more refined approach would involve identifying patients with specific CS profiles using tools like QST. For example, patients demonstrating both significant hyperexcitability (e.g., high TS) and deficient descending inhibition (e.g., low CPM) might derive the greatest benefit from a combination like a gabapentinoid plus an SNRI/TCA. In contrast, patients primarily exhibiting high TS might respond adequately to a gabapentinoid (or perhaps an NMDA antagonist), while those with predominantly deficient CPM might respond better to an SNRI or TCA alone. Tailoring combinations based on such mechanistic profiles represents a more targeted application of rational polypharmacy.

3. Dual Mechanism Opioids (μ-Opioid Agonist + NE Reuptake Inhibition)

Mechanism: These agents provide analgesia via two actions: moderate μ-opioid receptor agonism (dampening pain signal transmission) and inhibition of norepinephrine (and in some cases serotonin) reuptake, which enhances descending inhibition. By engaging these two pathways, they can help in central sensitisation pain where pure opioids might be insufficient and where boosting descending inhibition adds benefit.

Examples: Tramadol (weak μ-agonist + SNRI) and Tapentadol (stronger μ-agonist + norepinephrine reuptake inhibitor, not available in New Zealand). Tramadol is often considered a step-2 opioid and has evidence in neuropathic pain (Level B evidence: several trials support use, though typically as second-line) (Pharmacologic management of chronic neuropathic pain). Tapentadol (approved for diabetic peripheral neuropathy in some countries) has a higher μ load but also significant norepinephrine reuptake inhibition; it has shown efficacy in neuropathic pain and is an option when other therapies fail or are contraindicated.

Role in Therapy: Second-line (add-on or substitution). In a patient with partial relief from first-line combos, tramadol can be added for episodic severe pain spikes or if other first-line agents are contraindicated. It can be used concurrently with gabapentinoids or antidepressants. Tramadol 50–100 mg up to 4x daily can provide additional pain relief, particularly in mixed nociceptive-neuropathic presentations. Tapentadol (usually 50–100 mg extended-release twice daily) can be considered in more refractory cases or if tramadol is inadequate; its dual mechanism is mechanistically attractive for central sensitisation (addressing both central hyperexcitability and deficient inhibition).

Pure opioid analgesics (μ-agonists) like morphine or oxycodone should be avoided for chronic centralized pain – they provide no long-term benefit and can worsen central sensitisation via opioid-induced hyperalgesia with chronic use. They should be limited for specific scenarios such as post surgical pain management within a hospital setting.

Evidence: Tramadol has moderate evidence for neuropathic pain relief (NNT ~4–5 for 30% pain relief in short-term trials) and is included as a second-line agent in guidelines (Pharmacologic management of chronic neuropathic pain). Tapentadol’s efficacy in diabetic neuropathy was shown in RCTs leading to its approval; it may be as effective as oxycodone with potentially fewer CNS side effects due to the added NRI mechanism. Combining tramadol with an antidepressant or anticonvulsant can sometimes yield synergistic effects (and tramadol itself will augment descending inhibition like an SNRI). Caution: Tramadol and tapentadol should not be combined with other serotonergic drugs without careful monitoring (risk of serotonin syndrome). Long-term opioid use requires careful monitoring for tolerance, endocrine effects, and addiction risk. In general, in centrally sensitised pain, prefer tramadol/tapentadol over potent opioids to leverage their multimodal action, and use the lowest effective doses for the shortest necessary duration.

4. NMDA Receptor Antagonists (Inhibitors of Central Wind-up)

Mechanism: By blocking the NMDA receptor (a key glutamate receptor) on spinal and supraspinal neurons, these agents reduce the calcium influx and signaling that underlies central sensitisation (especially the wind-up phenomenon and long-term potentiation of pain pathways). NMDA antagonists can thereby diminish hyperalgesia and allodynia that are maintained by persistent glutamatergic activity.

Examples:

• Ketamine (and its isomer esketamine) – a potent NMDA antagonist with additional effects on opioid receptors and others. Overseas it is sometimes used intravenously (IV) in low sub-anesthetic doses for refractory pain (e.g. CRPS flares, severe neuropathic pain). It is very rare for that to be offered in New Zealand. Short-term ketamine infusions (over days) can produce significant temporary pain relief in CRPS, and sometimes a prolonged reduction in pain beyond the infusion period is observed due to “resetting” central sensitisation. Outpatient infusions or inpatient ketamine protocols are third-line options for severe, refractory central sensitisation pain. Ketamine is also available in oral and intranasal forms, but bioavailability is lower; those routes are used off-label in some chronic pain cases with careful supervision.
• Memantine – an oral NMDA antagonist (approved for Alzheimer’s disease) used off-label for pain. Memantine at 20 mg daily has shown benefit in fibromyalgia: a 6-month randomized trial found significant pain reduction and improved quality of life versus placebo. It is generally well tolerated. Memantine can be used as an add-on agent for patients with persistent pain hypersensitivity despite first-line treatments. Given its favorable safety profile, it is a reasonable second-line add-on for centrally sensitized fibromyalgia or neuropathic pain (Level B evidence in fibromyalgia, small trials in neuropathic pain).
• Dextromethorphan – an over-the-counter cough suppressant that at higher doses acts as an NMDA receptor blocker. It has been studied in neuropathic pain (mixed results) but is sometimes used off-label in combination with other agents (e.g. in doses of ~60–120 mg/day, divided). Dextromethorphan/quinidine (Nuedexta), approved for pseudobulbar affect, has anecdotal reports of benefit in central pain states (quinidine boosts dextromethorphan levels). This is a third-line consideration if other NMDA antagonists aren’t accessible.
• Others: Ketamine analogs (like dextroketamine or esketamine nasal spray) are being explored for chronic pain. Amantadine, an older NMDA antagonist, has limited evidence but was historically tried in chronic pain with mixed success.

Role in Therapy: Second- or third-line adjuncts. For a patient with ongoing dynamic allodynia or severe hyperalgesia, adding an NMDA antagonist can be useful. Oral memantine 5 mg titrated to 20 mg daily can be added to foundational therapy – especially in fibromyalgia or neuropathic pain with central sensitisation – to target the glutamatergic component. In refractory cases overseas patients are sometimes offered a ketamine infusion trial (e.g. 0.1–0.5 mg/kg/hr over several hours, repeated across days). This is very rare in New Zealand. Due to monitoring requirements and potential psychoactive side effects, IV ketamine is typically reserved for specialized pain centers and severe cases unresponsive to standard combos. If ketamine provides relief, some patients can be maintained on oral NMDA blockers thereafter.

Evidence: Moderate but promising evidence. Ketamine has shown efficacy in several small RCTs and uncontrolled studies in CRPS and neuropathic pain, though systematic reviews conclude evidence is still limited/weak for long-term benefit (A systematic review of ketamine for complex regional pain syndrome). Nonetheless, clinical experience supports its use in refractory cases, and short-term pain improvements are well documented (Level C evidence overall due to trial limitations). Memantine has Level B evidence in fibromyalgia and some positive data in neuropathic pain (e.g. phantom limb pain small trials). Dextromethorphan had mixed trial results in diabetic neuropathy (some studies showed modest benefit at high doses). Overall, NMDA antagonists are mechanistically sound and often justified by first principles even when evidence is not yet conclusive – central sensitisation is fundamentally an NMDA-mediated process, so blocking these receptors is a logical strategy when conventional therapies fall short.

5. Sodium Channel Blockers and Neural Stabilizers

Mechanism: These drugs reduce hyperexcitability by blocking voltage-gated sodium channels on neurons, thereby dampening ectopic discharges and spontaneous firing that contribute to neuropathic pain. By stabilizing neuronal membranes, they can help in conditions where peripheral or central neurons are hyperactive. Some agents in this class also have other actions (e.g. mixed ion channel effects).

Examples:

• Carbamazepine / Oxcarbazepine: Traditional anticonvulsants that block sodium channels. They are first-line for trigeminal neuralgia (a neuropathic pain with central sensitisation features in the trigeminal nucleus) and can be used in other neuropathic pains off-label. Oxcarbazepine may be better tolerated (less risk of agranulocytosis than carbamazepine). These are generally second-line in broader neuropathic pain due to side effect profile, but in a multi-drug regimen they may be considered for shooting, lancinating pains not controlled by gabapentinoids. Level B evidence for neuropathic pain (strong for trigeminal neuralgia; mixed results in polyneuropathy).
• Lamotrigine: Another anticonvulsant affecting sodium channels and glutamate release. While not broadly effective in all neuropathic pain, it has shown efficacy in central post-stroke pain and spinal cord injury pain in small RCTs. Lamotrigine 200–300 mg/day can be an add-on for refractory central pain syndromes (especially if the patient cannot tolerate other first-lines). It’s a third-line option (Level B/C evidence, condition-specific). It may also help mood symptoms as a bonus.
• Lidocaine (Local Anesthetic) and Mexiletine: IV lidocaine infusions can transiently reduce central sensitisation by systemically blocking sodium channels; they are sometimes used diagnostically or for short-term relief in neuropathic pain. Mexiletine is an oral analog of lidocaine used off-label for neuropathic pain (like refractory diabetic neuropathy or small fiber neuropathy). It has modest efficacy (some small trials support its use) and can be considered if first-line agents fail (third-line).
• Topiramate / Valproate: These broad-spectrum anticonvulsants (affecting sodium channels, GABA, etc.) have limited evidence in central sensitisation pain. Topiramate (up to 100 mg BID) has shown some benefit in small trials for neuropathic pain and fibromyalgia (and helps weight control if an issue), but side effects (cognitive slowing, paresthesias) often limit use. Valproate is occasionally used for migraine comorbid with central pain but is not a standard analgesic. Thus, these are generally not front-line but might be trialed in select cases (Level C evidence).

Role in Therapy: Adjunctive, based on pain phenotype. Use sodium channel blockers particularly when the pain involves paroxysmal shooting components or if there’s evidence of peripheral nerve injury contributing to central sensitisation. For example, a patient with CRPS or post-herpetic neuralgia who has burning pain might benefit from adding oxcarbazepine; a patient with central post-stroke pain might warrant a trial of lamotrigine. These are usually second or third-line add-ons once first-line combos (SNRI/gabapentinoid) are optimized. Titrate slowly to avoid toxicity (e.g. lamotrigine must be titrated over weeks to avoid rash).

Evidence: Varies by condition. Carbamazepine has high-quality evidence for trigeminal neuralgia (almost universally effective for that indication, Level A), but for other neuropathic pains evidence is moderate (some RCTs show benefit in diabetic neuropathy, others inconclusive). Oxcarbazepine had mixed trial results in diabetic neuropathy (some benefit at high dose). Lamotrigine has shown a statistically significant pain score reduction in central post-stroke pain vs placebo, and a systematic review suggests it may be moderately effective in that context. Lidocaine infusions have short-term efficacy in neuropathic pain (used in pain clinics for transient relief and to predict mexiletine response). Mexiletine’s evidence is limited but includes small positive studies in diabetic neuropathy. Overall, these agents are supported by rationale and some evidence, especially when classic first-line treatments are insufficient. They should be considered on a case-by-case basis (with particular benefit in peripherally triggered central sensitisation).

6. Alpha-2 Adrenergic Agonists (Enhancers of Descending Inhibition and Sympatholytics)

Mechanism: Drugs like clonidine and tizanidine activate α2-adrenergic receptors in the CNS, which leads to reduced sympathetic outflow and enhanced descending inhibition of pain. At the spinal level, α2 agonists reduce the release of excitatory neurotransmitters from primary afferents and hyperpolarize dorsal horn neurons, thereby diminishing pain transmission. They essentially mimic or augment the endogenous anti-nociceptive effect of norepinephrine (by directly stimulating the receptors rather than increasing NE levels as SNRIs do).

Examples:

• Tizanidine: a muscle relaxant and central α2-agonist. Off-label and not funded in New Zealand but available. Tizanidine has shown benefit in fibromyalgia – improving pain, sleep, and quality of life in some studies. In one open-label trial, tizanidine (2–12 mg at night, titrated) reduced fibromyalgia pain and fatigue and even lowered elevated cerebrospinal fluid substance P levels. Typical dosing is 2–4 mg at night, increasing to 8 mg TID as tolerated. Sedation and hypotension are common side effects. Tizanidine can be useful if muscle tension/spasms contribute to pain or if the patient has coexisting tension-type pain. It is considered a third-line adjunct for central sensitisation, particularly when sleep disruption is also an issue (since it can improve sleep).
• Clonidine: traditionally an antihypertensive, clonidine (oral or transdermal) can alleviate some neuropathic pain symptoms. It’s sometimes used in CRPS or neuropathic pain with sympathetically maintained components. Oral clonidine low doses (0.1 mg BID) may slightly reduce pain in diabetic neuropathy (evidence is mixed). More effectively, clonidine can be delivered intrathecally or epidurally in refractory pain (often combined with local anesthetics in pain pumps) to exploit its spinal α2 action. Clonidine patch (0.1–0.2 mg/day) is another off-label option for regional pain syndromes like CRPS, providing a slow-release systemic effect that may reduce hyperalgesia without significant sedation.
• Dexmedetomidine: a more selective α2 agonist (used IV for sedation) has emerging use in pain (e.g. as an adjunct in anesthesia for opioid-sparing). Oral/transdermal formulations are experimental for chronic pain. Not yet standard, but future use is possible.

Role in Therapy: Adjunct for refractory pain or specific phenotypes. Consider adding tizanidine for a patient with fibromyalgia or widespread central pain who also has muscle tightness or very poor sleep – it can be a helpful bedtime medication for pain and sleep maintenance (and can be combined with other first-line agents). Clonidine or its patch can be tried in CRPS or in patients with suspected sympathetic contribution (cold, cyanotic painful limb, etc.), or generally as a trial if other options are exhausted. These drugs are generally third-line due to side effects (sedation, dizziness, blood pressure drops), but their unique mechanism can benefit certain individuals. They should be started at low doses and titrated carefully.

Evidence: Limited (Level C) for most chronic pain indications, but supported by physiological rationale. Tizanidine’s largest support comes from small trials and case series in fibromyalgia (one study showed improved pain and sleep vs placebo, but larger RCT data are lacking). Still, a notable observation was the reduction of CSF substance P with tizanidine, suggesting a direct effect on central sensitisation biochemistry. Clonidine had some positive results in older studies for diabetic neuropathy and painful plexus neuropathies, but at the cost of hypotension in some patients. Intrathecal clonidine is an evidence-backed component in refractory cancer pain or neuropathic pain management (often in combination with opioids, reducing pain and opioid requirements). Overall, while not first-line, α2-agonists “may provide benefit for FM patients by reductions in pain, improvement in sleep, and improvement in QOL”, and are reasonable to trial when conventional options don’t fully suffice.

7. Microglial and Neuroinflammation Modulators

Mechanism: These therapies target the immune-like cells in the CNS (microglia and astrocytes) that release pro-inflammatory cytokines and neuroexcitatory substances during chronic pain. By modulating glial activity or inflammatory signaling, they aim to reverse the neuroimmune component of central sensitisation. This is a relatively novel approach, arising from evidence of neuroinflammation in conditions like fibromyalgia (e.g. elevated cytokines, glial markers).

Examples:

• Low-Dose Naltrexone (LDN): Naltrexone is an opioid receptor antagonist, but at much lower doses (e.g. 1–4.5 mg nightly) it paradoxically has analgesic and anti-inflammatory effects. Proposed mechanisms include: blockade of microglial Toll-like receptors (TLR4) leading to reduced glial activation, and rebound increase in endorphin levels. LDN has been explored in fibromyalgia and CRPS. Some small studies and case series reported meaningful pain reductions and improved fatigue in fibromyalgia patients. However, the first larger RCT (12 weeks of LDN 6 mg in fibromyalgia) did not show a significant benefit over placebo. A recent systematic review concluded that LDN appears safe and possibly effective for fibromyalgia symptom management, but evidence remains limited. Despite mixed data, many clinicians consider a trial of LDN in refractory central sensitisation syndromes because of its benign safety profile. Typically 1.5 mg is started at night, increasing to 4.5 mg nightly. It is an off-label, third-line adjunct when conventional treatments yield suboptimal results. If effective, it may reduce pain and also improve fatigue or cognitive symptoms in some patients (as noted anecdotally in fibromyalgia).
• Minocycline: A tetracycline antibiotic that also inhibits microglial activation and suppresses pro-inflammatory cytokines in the CNS. In animal models of neuropathic pain, minocycline prevents or reduces central sensitisation. In human RCTs, it seems to be more effective for chemical or toxic based neuropathic pain such as diabetic neuropathy, leprosy neuropathy, and chemotherapy induced neuropathy; rather than compressive types of neuropathy like radicular pain and carpal tunnel syndrome. Minocycline may be considered in diffuse central sensitisation pain or neuropathic pain where neuroinflammation is suspected. Dose is usually 100 mg twice daily. Side effects (dizziness, nausea, skin hyperpigmentation with long use) must be monitored. Given its novel target and safety, it’s a reasonable mechanism-based add-on (Level C evidence so far) for refractory cases or when other first-line meds are contraindicated.
• Palmitoylethanolamide (PEA): PEA is widely available as a dietary supplement or "dietary food for special medical purposes" that has some supportive clinical evidence.
• Other Immunomodulators: Several other approaches are under investigation. Examples include glial attenuators like ibudilast (an experimental CNS glial inhibitor) which has shown some benefit in preliminary chronic pain trials, and anti-cytokine therapies (like IL-6 or TNF inhibitors) which are not yet proven in central pain except certain cases (e.g. TNF inhibitors in some CRPS case reports). Intravenous immunoglobulin (IVIG) has been used in CRPS or small-fiber neuropathy with some success in small trials, possibly via immunomodulation, but it’s costly and reserved for severe refractory immune-mediated cases. These are beyond routine use but illustrate the principle of targeting neuroinflammation.

Role in Therapy: Adjunctive, typically third-line. These agents are added for patients who have not achieved adequate relief from the more proven therapies above, especially if the side effect burden is limiting further escalation of those. LDN can be added without interfering with other drugs (except avoid simultaneous opioid use, as naltrexone will block opioid receptors). It may take 4–8 weeks to gauge LDN’s effect. Minocycline can be added alongside other analgesics as well. Because these are off-label and evidence is emerging, they are often used in consultation with or by pain specialists. They are reasonable to consider when conventional pathways (neural and neurotransmitter targets) have been addressed but pain remains, hinting that neuroimmune processes might be sustaining sensitisation.

Evidence: Limited but growing. For LDN, aside from the negative 2023 trial, prior smaller studies reported that ~57% of fibromyalgia patients had a significant reduction in symptoms on LDN vs placebo. A systematic review in 2023 found that overall LDN appears effective and safe in fibromyalgia, but high-quality evidence is lacking and larger trials are needed. Given the inconsistent results, the level of evidence is low (C), but the potential upside (with minimal risk) justifies a trial in appropriate patients. Minocycline’s evidence is also early-stage but is strongest for neuropathy due to diabetes and chemotherapy. Overall, while traditional RCT evidence is limited, neuroimmune modulators are included here by neurophysiological reasoning: they address a facet of central sensitisation not touched by other drug classes, and early research is encouraging.

8. Cannabinoids (Endocannabinoid System Modulators)

Mechanism: Cannabinoid agents (derived from Cannabis or synthetic) activate cannabinoid receptors (CB1 and CB2) in the nervous system. CB1 receptors in the brain and spinal cord modulate neurotransmitter release (reducing glutamate and other excitatory transmitters, and activating descending inhibition), while CB2 receptors (mainly peripheral and on microglia) can reduce neuroinflammation. The endocannabinoid system is a key regulator of pain and central sensitisation, so some clinicians feel that augmenting it can help alleviate chronic pain. However the evidence is extremely poor with alarmingly high NNTs, and this class of drugs is not recommended by the Australasian Pain Faculty.

9. Histamine Receptor Antagonists and Mast Cell Stabilizers

Mechanism: Histamine, released primarily from mast cells during inflammation or tissue injury, plays a complex role in pain signaling. It can directly activate nociceptors and contributes significantly to neurogenic inflammation through a positive feedback loop involving sensory nerves and mast cells. Histamine exerts its effects via four receptor subtypes (H1-H4). H1 receptor activation is generally pro-nociceptive, contributing to hyperalgesia, vasodilation, and itch. The role of H2 receptors is more complex, with involvement in gastric acid secretion but also potentially contributing to neuropathic pain mechanisms (e.g., via Nav1.8 channel upregulation) and visceral hypersensitivity. Mast cells, strategically located near nerves, release a host of mediators beyond histamine (e.g., serotonin, proteases, cytokines, NGF) upon activation by various stimuli (including neuropeptides), amplifying inflammation and sensitizing nociceptors. Targeting histamine receptors or stabilizing mast cells represents another potential avenue for modulating pain, particularly where neuroinflammatory processes are prominent.

Examples:

• Second-Generation H1 Receptor Antagonists (e.g., Loratadine, Cetirizine, Fexofenadine):
  • Mechanism: These agents selectively block peripheral H1 receptors with minimal CNS penetration, reducing histamine-mediated nociceptor sensitisation and vascular changes. Some may also possess independent anti-inflammatory properties.
  • Evidence: Fexofenadine reduced mechanical allodynia in a tibial nerve transection neuropathic pain rat model, suggesting a role for peripheral H1 receptors as fexofenadine doesn't cross the BBB. Loratadine may have a role in treating pegfilgrastim (G-CSF)-induced bone pain. Loratadine also showed potential benefit in mitigating vinca alkaloid-induced neuropathy in one trial. Evidence for cetirizine and fexofenadine as primary analgesics is very limited, mainly confined to itch relief in allergic conditions. Overall, robust evidence supporting broad analgesic use for chronic neuropathic or nociplastic pain is lacking.
  • Role in Therapy: Primarily adjunctive for specific niches like G-CSF-induced pain or potentially pain with a significant allergic/histaminergic component. Not considered standard therapy for central sensitization pain.
• H2 Receptor Antagonists (e.g., Famotidine, Ranitidine):
  • Mechanism: Block H2 receptors, primarily known for reducing gastric acid secretion. Famotidine has poor CNS penetration. One preclinical study suggested peripheral H2 blockade might reduce neuropathic pain by inhibiting Nav1.8 upregulation in sensory neurons, though other studies in different models found it ineffective where CNS access seemed important. Ranitidine is not longer available in New Zealand, but was more effective than famotidine in the rat tibial nerve transection model.
  • Evidence: Clinically established for relieving pain associated with acid-related gastrointestinal disorders (ulcers, GERD, dyspepsia) and used for gastroprotection with NSAIDs. There is no robust clinical evidence supporting famotidine as a primary analgesic for neuropathic, nociplastic, or other non-acid-related pain conditions.
  • Role in Therapy: Standard for acid-related GI pain. Not recommended for the primary treatment of central sensitization pain syndromes.
• Mast Cell Stabilizers (e.g., Ketotifen, Sodium Cromoglycate):
  • Mechanism: Inhibit mast cell degranulation, preventing the release of histamine and a broad spectrum of other pro-inflammatory and algogenic mediators (serotonin, proteases, cytokines, NGF). This interrupts the mast cell-nerve amplification loop. Ketotifen also possesses potent H1 antagonist activity.
  • Evidence: Preclinical studies consistently show efficacy for ketotifen and sodium cromoglycate in inflammatory rat pain models (formalin, CFA) and conditions where mast cell activation is key (e.g., endometriosis model for ketotifen, sickle cell model for cromoglycate). Notably, ketotifen's efficacy in these models was dependent on the presence of mast cells and it was ineffective in a model of established neuropathic pain (spared nerve injury), suggesting specificity for mast cell-driven processes. Clinically, ketotifen has shown promise in reducing visceral hypersensitivity and symptoms in IBS, treating chronic cluster headache, and relieving neurofibroma-associated pain/itch. A case series suggested benefit in adolescent CWP, but a recent fibromyalgia trial was negative. Sodium cromoglycate has pilot data supporting potential use in IBS but lacks extensive clinical analgesic trials.
  • Role in Therapy: Considered third-line or adjunctive, primarily for conditions with suspected mast cell involvement (e.g., IBS with visceral hypersensitivity, potentially endometriosis-related pain, cluster headache, specific inflammatory phenotypes). Their role in broad central sensitization syndromes like fibromyalgia remains uncertain and requires further investigation.

Evidence: Very limited: Despite a clear role for histamine and mast cells in pain pathophysiology, the current evidence for using most antihistamines and mast cell stabilizers as primary analgesics for chronic neuropathic and nociplastic pain is limited and largely confined to specific niche applications (e.g., loratadine for G-CSF pain, H2 blockers for GI pain, ketotifen for IBS/cluster headache). They are generally not recommended as foundational treatments for central sensitisation but may be considered as adjunctive therapies in specific clinical contexts where their mechanisms align with suspected underlying drivers.

10. Other and Experimental Pharmacotherapies

Several other pharmacologic approaches may be used in specialized contexts:

• Topical Agents: For patients with a localized neuropathic pain component (e.g. post-herpetic neuralgia or CRPS-confined to a limb), high-concentration capsaicin 8% patch or lidocaine 5% patches can reduce peripheral input driving central sensitisation. These topical treatments (first-line for localized neuropathic pain in some guidelines) reduce nociceptive signaling from peripheral nerves, which may secondarily diminish central sensitisation. They can be used as add-ons (e.g. lidocaine patch over an area of allodynia while systemic drugs address central mechanisms). While primarily acting peripherally, their inclusion in multimodal therapy can be justified as part of a holistic approach to reduce overall pain signaling.
• Intrathecal Therapies: This is not generally offered in New Zealand. In severe refractory cases (typically managed by pain specialists), intrathecal drug delivery can directly target the spinal cord dorsal horn. Ziconotide, a calcium channel blocker (N-type) derived from cone snail toxin, is given intrathecally for refractory neuropathic pain and has no cross-tolerance with opioids. It can substantially reduce pain by inhibiting neurotransmitter release in the dorsal horn, essentially blocking central sensitisation at its entry point. Intrathecal baclofen (a GABA_B agonist) can reduce central pain and spasticity in spinal cord injury or MS. Intrathecal clonidine (as mentioned) and even ketamine (off-label via intrathecal routes) have been tried. These invasive options are not generally available in New Zealand.
• Enhancement of Inhibitory Neurotransmitters: While no specific oral drug boosts GABA or glycine transmission solely for pain, benzodiazepines (like clonazepam) are sometimes used at night for neuropathic pain with comorbid anxiety or for central pain syndromes with parasthesias (clonazepam has shown some efficacy in restless legs and might mildly help pain). However, benzodiazepines are not routinely recommended due to tolerance and lack of evidence in chronic pain. Acamprosate, a modulator of glutamate/GABA, and baclofen oral (GABA_B agonist) have minimal evidence but could be tried if spasticity or myoclonus is present with pain.
• Novel Emerging Therapies: Numerous targets are under research: e.g. NK-1 (substance P) antagonists, gene therapies for ion channels, TRPV1 antagonists (or agonists like capsaicin analogs), CGRP antagonists (approved for migraine, being explored in other pain), etc. These are not yet guideline-level treatments but may play a role in future central sensitisation management.

Treatment Algorithm and Tiers of Therapy

Drawing on the above, a stepwise multimodal treatment algorithm for central sensitisation pain in adults is as follows. Monitor pain reduction, patient function, and side effects frequently (every 2–4 weeks during titration). If the combination is tolerated, aim for moderate dose ranges of each rather than maximal dose of one – this provides synergy with fewer adverse effects. Expect partial relief; complete pain elimination is rare, but goal is significant improvement in pain (≥30-50% reduction) and function.

Use lower doses when layering medications. This helps manage side effect burden. This approach is supported by pain specialist consensus: “using lower dose combination therapies with different mechanisms of action” can improve pain relief while minimizing toxicity. Many guidelines now acknowledge combination therapy as an option if monotherapy is inadequate, despite limited formal trial evidence for every combination. In practice, combination therapy is often necessary – as noted, “many patients have insufficient pain relief on monotherapy” and experts often resort to polypharmacy for neuropathic pain.

First-Line (Foundational Therapy)

Initiate treatment with a single agent from an established first-line class targeting a core CS mechanism (neuronal hyperexcitability or descending modulation deficiency). Assess initial response and tolerability.

• TCA: (e.g., Nortriptyline start 10-50 mg nocte). Targets descending NE/5-HT inhibition + VGSCs. Consider if comorbid depression or insomnia. Use lower doses and caution in elderly, cardiac disease. Potential Phenotype Guidance: Consider if deficient descending inhibition (low CPM) is suspected, widespread pain can be a clue.  
• Gabapentinoid: (e.g., Pregabalin start 25-75 mg BID, titrate q3-7d up to 150-300 mg BID; Gabapentin start 100-300 mg TID, titrate q3-7d up to 600-1200 mg TID). Targets α2δ subunit (↓ excitatory NT release). May help comorbid anxiety. Adjust dose for renal impairment. Monitor for misuse potential. Potential Phenotype Guidance: Consider if neuronal hyperexcitability (high TS, evoked pain) is suspected.
• SNRI: If duloxetine ever becomes available in New Zealand then this will be a good option. Venlafaxine does not have published evidence and high doses are needed to target the NET receptors (Duloxetine start 30 mg daily, titrate q1-2wk to 60-120 mg daily; Venlafaxine XR start 37.5-75 mg daily, titrate q1-2wk up to 150-225 mg daily). Targets descending NE/5-HT inhibition. Duloxetine is often better tolerated than TCAs. Monitor BP with venlafaxine. Caution in severe renal/hepatic impairment (duloxetine). Potential Phenotype Guidance: Consider if deficient descending inhibition (low CPM) is suspected.

Consider beginning with two different first-line classes in challenging cases.

Second Line (Combination Therapy)

Improve efficacy if Step 1 monotherapy provides inadequate relief (e.g., <30-50% improvement) despite an adequate trial, or if dose-limiting side effects prevent reaching effective monotherapy doses. Add a second agent from a different first-line class targeting a complementary mechanism.

• Gabapentinoid + SNRI/TCA: This combination addresses both potential neuronal hyperexcitability (via α2δ modulation) and deficient descending inhibition (via NE/5-HT reuptake inhibition). Add the second agent at a low starting dose and titrate slowly while maintaining the first agent at its previously optimized/tolerated dose. The goal is often to achieve efficacy using moderate doses of both agents, rather than maximizing the dose of either one, potentially improving tolerability. Potential Phenotype Guidance: Theoretically most beneficial for patients exhibiting features of both hyperexcitability (e.g., high TS) and impaired inhibition (e.g., low CPM).  
• Alternative Strategy (Switch): If the initial first-line agent was poorly tolerated even at low doses, switch to a different first-line agent from another class (e.g., switch from TCA to Gabapentinoid, or SNRI to TCA) and repeat the monotherapy trial (Step 1).

Monitoring: Increased vigilance is required for additive adverse effects (e.g., sedation, dizziness, cognitive effects, particularly with Gabapentinoid + TCA). Screen for potential drug interactions (e.g., avoid TCA + SNRI due to serotonin syndrome risk ) using resources like the BNF or drug interaction checkers. Re-evaluate efficacy, function, and tolerability after 4-8 weeks on a stable combination regimen.

Third-Line (Augmentation to Combination Therapy)

If the patient has some benefit but still clinically significant pain, add a third agent targeting a new mechanism. This tier of treatment has very limited clinical evidence. The choice depends on the symptom profile:

• If persistent temporal summation: consider memantine starting at 5mg titrating by 5mg weekly to 20 mg to target NMDA-mediated sensitisation. Monitor for dizziness.
• If sleep remains poor and pain is worse at night: add clonidine, non-funded tizanidine 2–4 mg at bedtime, or switch nortriptyline to amitriptyline to improve sleep and pain.
• For localized intense pain areas: add non-funded topical lidocaine (12 hours on/off), lidocaine patches if they become available, or a periodic capsaicin 8% patch application if they become available, to reduce peripheral nociceptive input fueling central sensitisation.
• For prominent nociplastic features (widespread pain, fatigue, multisensory hypersensitivity): consider adding low dose naltrexone. Start 0.5-1.5mg at night, titrate every 1-2 weeks up to maximum of 4.5mg. Confirm no concurrent opioid use. Alternatively consider minocycline 100mg twice daily (particularly if there has been a partial response to steroids or NSAIDs), or PEA 3 x 400mg per day.
• For paroxysmal pain: If the pain behaves like a channelopathy such as ongoing peripheral neuronal hyperexcitability particularly paroxysmal pain, consider a sodium channel blocker like carbamazepine. This is first line in trigeminal neuralgia, but can be speculatively considered for other neuropathic pain conditions with a similar phenotype.
• For visceral hypersensitivity, evidence of neurogenic inflammation, or multiple drug reactions: Consider adding loratadine 10-40mg daily plus sodium cromoglycate 200mg twice daily, or ketotifen alone starting 1mg nocte titrating to max 2mg twice daily (requires compounding lab to make up from ketotifen eye drops).
• For spinal cord spasticity: Consider

Reevaluate after introducing the add-on. So 5-20mg tds.me patients might achieve some relief with a triple therapy regimen (e.g. nortriptyline+ pregabalin + memantine). Adjust doses within tolerability to maximize benefit.

Agents not Recommended

• Ketamine: IV ketamine infusions are not generally available in New Zealand and there is no reliable access to oral formulations. It is not generally appropriate in community based pain management.
• Opioids: Avoid if at all possible due to Opioid Induced Hyperalgesia. If an opioid is being considered then tramadol has the most evidence. However it should not be used regularly.
• Medicinal Cannabis: Essentially proven to be ineffective and potential for Cannabis Induced Sensitisation.
• Benzodiazepines: Due to dependency and lack of efficacy

If significant pain persists then they are likely resistant to pharmacological management

Resources

Central sensitisation - Nijs 2021.pdf - 656 KB (f)