Managing neuropathic pain in bipolar disorder

Introduction

Neuropathic pain is a complex condition, resulting from disease or damage to the somatosensory nervous system^​1​. Causes of neuropathic pain are multifactorial and heterogenous, encompassing metabolic disorders (e.g. diabetic neuropathy), viral infections (e.g. post-herpetic neuralgia), autoimmune diseases (e.g. multiple sclerosis), chemotherapy induced neuropathy, traumatic injuries (e.g. spinal cord injury), inflammatory conditions, hereditary neuropathies and channelopathies^​2,3​.

Patients typically present with clinical features such as pain from a stimulus that does not normally provoke pain (i.e. allodynia), increased response to a stimulus that is normally painful (i.e. hyperalgesia) and abnormal sensory perception (i.e. paraesthesia), which can substantially impair quality of life and adversely affect mental health^​2​. The results of an analysis of 148,828 participants in the UK, published in 2023, highlighted a chronic pain prevalence of 51.1%, with 9.2% classified as neuropathic in origin^​4​. Standard management of neuropathic pain involves pharmacological interventions (e.g. antidepressants and anticonvulsants) and non-pharmacological approaches, such as physical or psychological therapies^​2,5​.

Bipolar disorder is a serious mental illness (SMI) — affecting around 2% of the global population — which is characterised by episodic shifts between mania and depression^​6​. Treatment requires dynamic and phase-specific management, often combining pharmacotherapy and psychotherapy^​6​. Notably, studies have revealed evidence of a high prevalence of pain and chronic pain among patients with bipolar disorder. A large systematic review and meta-analysis, published in 2014, included 171,352 patients with bipolar disorder and highlighted that around 23.7% of patients with bipolar disorder experience chronic pain, yet this comorbidity remains underacknowledged in clinical practice^​7​. Patients with SMI are disproportionately vulnerable to underdiagnosed and undertreated pain. These patients also often experience inequities in healthcare access and delivery^​8,9​.

The neuropharmacological overlap between neuropathic pain treatments and mood stabilisers poses unique challenges, including the potential for mood destabilisation, drug–drug interactions (DDIs) and complications arising from polypharmacy^{​2,5,10,11​}. Pharmacists have a critical role in mitigating these risks through promoting evidence-based medicine, medication choice and review, as well as patient counselling^{​12–14​}. However, clinical management requires a coordinated, multidisciplinary approach, involving pharmacists, physicians, psychiatrists and nurses, to ensure holistic, patient-centred management^​15​. 

This article aims to support healthcare professionals to make informed, integrated clinical decisions that optimise outcomes for patients with comorbid bipolar disorder and neuropathic pain.

Pathophysiology and clinical intersection

Neuropathic pain arises from a variety of aetiological factors and is frequently accompanied by psychiatric comorbidities, such as anxiety, stress-related symptoms and major mood disorders^​7​. Despite this well-established association, the precise physiological mechanisms linking neuropathic pain and affective disorders are not completely understood, particularly in the absence of definitive biomarkers^​16​. Emerging evidence points towards several shared pathophysiological mechanisms between neuropathic pain and affective disorders, including dysregulation of inflammatory pathways, altered neurotransmission and stress-axis dysfunction that may contribute to both pain and mood disturbance^{​17–19​}. See Figure for more information^{​17–20​}.

Clinically, the pathophysiological interactions between bipolar disorder and chronic pain are bidirectional: chronic pain can exacerbate depressive and mixed mood episodes in bipolar disorder, while mood instability can enhance pain perception through affective dysregulation and cognitive distortions^​21​. The comorbidity between neuropathic pain and affective disorders appears to share mechanisms and clinical intersections, which highlights the necessity for further research to help develop integrated therapeutic strategies to target both nociceptive and affective symptomatology.

Pharmacological treatment challenges

The management of neuropathic pain in patients with bipolar disorder presents significant pharmacological challenges. Clinicians must strike a delicate balance between achieving adequate analgesia and maintaining mood stability, while minimising risks of DDIs, adverse effects and polypharmacy. These challenges are discussed in the following sections, with clinical examples provided.

Antidepressants, such as amitriptyline, are frequently used as first-line agents for neuropathic pain; however, their use in patients with bipolar disorder carries an increased risk of inducing manic or hypomanic episodes, particularly in patients not concomitantly treated with a mood stabiliser^{​22–24​}. For example, a patient with bipolar disorder treated with antidepressants for diabetic neuropathy may experience mood destabilisation, requiring urgent psychiatric intervention, as well as increased pain owing to withdrawal of the causative agent. Similarly, anticonvulsants, such as carbamazepine, offer dual benefit by targeting both neuropathic pain and mood symptoms. However, enzyme-inducing properties can reduce plasma concentrations of antipsychotics, such as quetiapine, which may lead to subtherapeutic levels and diminished efficacy, requiring dose adjustments or substitutions^​25​. 

Mood stabilisers, such as lithium, remain a cornerstone maintenance treatment in bipolar disorder but will introduce complexity when combined with neuropathic pain agents, such as duloxetine or gabapentin, owing to increased polypharmacy burden. This burden raises risks of adverse drug reactions and DDIs, which may potentiate a prescribing cascade (i.e. adding medicines to treat side effects caused by other medicines)^​25,26​. Gabapentinoids, including pregabalin and gabapentin, generally have a lower risk of mood destabilisation, with limited evidence suggesting they precipitate mania; however, their side effects and misuse potential require careful monitoring^{​27–31​}.

Overall, effective management of neuropathic pain in patients with bipolar disorder requires a highly individualised approach. Treatment decisions should weigh analgesic benefit against psychiatric safety, with close collaboration between psychiatry, pain medicine and pharmacy. Regular monitoring for mood changes, medication interactions and emerging side effects is essential to optimising outcomes while minimising harm. 

Evidence-based practical management approaches

Current UK guidelines highlight the importance of tailoring pain management to the underlying aetiology, symptom severity and individual patient context^​5​. In guidance, updated in 2020, the National Institute for Health and Care Excellence (NICE) emphasises a shared decision-making approach, ensuring that patients are actively involved in discussion about pharmacological treatment options, including the expected benefits, potential side effects and titration regimens^​5​. This patient-centred strategy is particularly important in this clinical context as treatment decisions must consider efficacy of pain interventions versus the risk of mood destabilisation. The Table ^{​23,24,27–33​} summarises the pharmacological options for neuropathic pain recommended in the UK (excluding trigeminal neuralgia). In the case of trigeminal neuralgia, carbamazepine remains the preferred first-line therapy, with specialist referral advised when contraindications exist or when treatment proves ineffective^​5​.

Pharmacological interventions should commence when psychiatric stability is established, which includes stable mood, adherence to mood stabilisers and ongoing psychiatric monitoring^{​22,34,35​}. In patients with bipolar disorder, antidepressants, such as amitriptyline and duloxetine, should be used cautiously and preferably adjunctively with mood stabilisers or second-generation antipsychotics to mitigate manic switching^​23,24​. Evidence does not strongly implicate gabapentinoids in mania induction, while some research even explores their adjunctive use in mood disorders^{​27–30​}. However, gabapentinoid agents carry potential for misuse. It is important to ensure continuity of care under a single service, which may aid with continuous risk assessment, regular review and clear treatment boundaries to prevent multiple avenues of accessibility and mitigate misuse^​5,31​.

If initial therapy fails, another of the remaining three first-line agents may be trialled. Consider switching if second and third first-line drugs are also not effective or tolerated^​5​. Choice should be informed by tolerability, side effect profile, comorbid conditions and patient preference^​5​. Ongoing monitoring is essential to ensure analgesic efficacy, safety and psychiatric stability. Clinical reviews should include assessment of pain control, functional impact, mood symptoms, adverse effects, signs of misuse and continued need for treatment^​5​. Clinicians should also ensure that titrations are gradual with close surveillance for early signs of mood relapse (e.g. insomnia, elevated mood, grandiosity). Carbamazepine may be used in trigeminal neuralgia; however, its utility as a mood stabiliser is limited, and DDIs are frequent, warranting close interdisciplinary oversight^{​36–38​}.

Although research to date has not explicitly explored cognitive behavioural therapy (CBT) for neuropathic pain in bipolar disorder, evidence supports CBT effectiveness in each condition individually. CBT reduces neuropathic pain intensity and interference^​39,40​. Reviews and meta-analyses have confirmed its efficacy in decreasing manic and depressive symptoms, relapse risk and improving functioning in bipolar disorder^​41,42​. Adjunctive non-pharmacological interventions, including CBT, mindfulness and structured rehabilitation, offer low-risk support and may improve both pain and mood outcomes^{​42–44​}. These findings suggest CBT may be a promising adjunct for patients with comorbid bipolar disorder and neuropathic pain; however, further research is needed to evaluate its effectiveness in this specific population. 

Future directions

Despite advancements in neuropathic pain management, there remains a dearth of evidence directly relating to patients with comorbid bipolar disorder and neuropathic pain. Many randomised controlled trials investigating neuropathic pain systematically exclude participants with SMI, limiting the generalisability of findings to this patient population^​45,46​.

An area of increasing research relates to glutamatergic agents, such as ketamine and esketamine, which have demonstrated short-term analgesic effects in neuropathic pain, as well as rapid antidepressant effects in mood disorders; however, case reports of ketamine-induced mania highlight significant safety concerns in bipolar disorder, necessitating further investigation^{​47–50​}. Other glutamatergic modulators, such as memantine, have been investigated for neuropathic pain; however, existing evidence remains inconclusive and lacks evaluation of psychiatric outcomes^{​51–53​}.

Conclusion

The intersection of bipolar disorder and neuropathic pain represent a complex clinical challenge, which is characterised by overlapping pathophysiology, pharmacological contraindications and an insufficient tailored evidence base. Both conditions independently impose significant burdens; yet, their comorbidity remains under-acknowledged and inadequately treated. Effective management requires patient-centred, multidisciplinary strategies, prioritising psychiatric stability and shared decision-making, as well as cautious evidence-based pharmacotherapy, prioritising low-risk agents with close monitoring. Non-pharmacological adjuncts, such as CBT therapy and rehabilitation, offer valuable, low-risk benefits. Bridging the evidence gap with inclusive research and integrated care models is essential to delivering safe, effective and equitable treatment for patients affected by both bipolar disorder and neuropathic pain.