Recommendations for research

1 Monotherapy versus combination therapy for treating neuropathic pain

What is the clinical effectiveness, cost effectiveness and tolerability of pharmacological monotherapy compared with combination therapy for treating neuropathic pain?

Why this is important

Combination therapy is commonly prescribed for neuropathic pain. It may also be a helpful option as a stepwise approach if initially used drugs are insufficient at reducing pain. Combination therapy may also result in better tolerability because smaller doses of individual drugs are often used when combined with other drugs. However, there is a lack of trial evidence comparing the clinical and cost effectiveness and tolerability of different drug combinations. Further research should be conducted as described in table 1 below.

**Table 1 Monotherapy versus combination therapy for treating neuropathic pain**
Criterion	Explanation
Population	Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include: Central neuropathic pain/central pain Complex regional pain syndromes Compression neuropathies/nerve compression syndromes Facial neuralgia HIV-related neuropathy Mixed neuropathic pain Multiple sclerosis Neurogenic pain Neuropathic cancer pain/cancer pain Neuropathic pain Painful diabetic neuropathy/diabetic neuropathy Peripheral nerve injury Peripheral nervous system disease/neuropathies Phantom limb pain Polyneuropathies Post-amputation pain Post-herpetic neuralgia Post-stroke pain Post-treatment/post-surgery/post-operative pain Radiculopathies/radicular pain Spinal cord diseases Spinal cord injury Trigeminal neuralgia
Intervention(s)	Pharmacological agents as monotherapy or combination therapy. The pharmacological agents include: Amitriptyline Clomipramine Dosulepin (dothiepin) Doxepin Imipramine Lofepramine Nortriptyline Trimipramine Citalopram Escitalopram Fluoxetine Paroxetine Sertraline Duloxetine Mirtazapine Reboxetine Trazodone Venlafaxine Carbamazepine Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Pregabalin Valproate Topiramate Buprenorphine Co-codamol Co-dydramol Dihydrocodeine Fentanyl Morphine Oxycodone Oxycodone with naloxone Tapentadol Tramadol Cannabis sativa extract Flecainide 5-HT₁-receptor agonists Topical capsaicin Topical lidocaine
Comparator(s)	Any of the above listed pharmacological agents as monotherapy compared with any combinations of the above listed pharmacological agents as combination therapy.
Outcome(s)	Patient-reported global improvement (on a 7-point scale) Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale) At least 30% and 50% pain reduction (on a 11-point Numerical rating scale [NRS] scale) Mean change from baseline pain scores (on a 11-NRS scale) Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design	Parallel triple-blinded randomised controlled trial of at least 12‑weeks' study period (they should not have enriched enrolment). All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation. Baseline pain scores between arms should be equal and clearly documented. Concomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs. Rescue pain medications should either not be allowed or, if used, their use should be accurately documented.

2 Relationship between symptoms, cause of neuropathic pain and its treatment

Is response to pharmacological treatment predicted more reliably by underlying aetiology or by symptom characteristics?

Why this is important

There is little evidence about whether certain symptoms that present in healthcare settings, or whether different neuropathic pain conditions with different aetiologies, respond differently to different treatments. Current evidence is typically focused on particular conditions and is limited to particular drugs. Further research should be conducted as described in table 2 below.

**Table 2 Relationship between symptoms, cause of neuropathic pain and its treatment**
Criterion	Explanation
Population	Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include: Central neuropathic pain/central pain Complex regional pain syndromes Compression neuropathies/nerve compression syndromes Facial neuralgia HIV-related neuropathy Mixed neuropathic pain Multiple sclerosis Neurogenic pain Neuropathic cancer pain/cancer pain Neuropathic pain Painful diabetic neuropathy/diabetic neuropathy Peripheral nerve injury Peripheral nervous system disease/neuropathies Phantom limb pain Polyneuropathies Post-amputation pain Post-herpetic neuralgia Post-stroke pain Post-treatment/post-surgery/post-operative pain Radiculopathies/radicular pain Spinal cord diseases Spinal cord injury Trigeminal neuralgia
Intervention(s)	Any pharmacological agents as monotherapy or combination therapy (see research recommendation B1).
Comparator(s)	Same pharmacological agents chosen as the main treatments of interest but compare the treatment response across different groups of participants with different neuropathic pain conditions or underlying aetiology.
Outcome(s)	Patient-reported global improvement (on a 7-point scale) Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale) At least 30% and 50% pain reduction (on a 11-NRS scale) Mean change from baseline pain scores (on a 11-NRS scale) Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design	Prospective cohort study All participants should have a 'wash-out' period before assessment for inclusion in the study. Baseline pain scores between arms should be equal and clearly documented. Concomitant medications should not be allowed, or should be restricted and maintained at stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs. Rescue pain medications either not be allowed or, if used, their use should be accurately documented.

3 Carbamazepine for treating trigeminal neuralgia

What is the clinical and cost effectiveness of carbamazepine as initial treatment for trigeminal neuralgia compared with other pharmacological treatments?

Why this is important

Carbamazepine has been the standard treatment for trigeminal neuralgia since the 1960s. Despite the lack of trial evidence, it is perceived by clinicians to be efficacious. Further research should be conducted as described in table 3 below.

**Table 3 Carbamazepine for treating trigeminal neuralgia**
Criterion	Explanation
Population	Adults with a diagnosis of trigeminal neuralgia.
Intervention(s)	Carbamazepine as monotherapy.
Comparator(s)	Any of the below listed pharmacological agents as monotherapy or combinations. The pharmacological agents include: Amitriptyline Clomipramine Dosulepin (dothiepin) Doxepin Imipramine Lofepramine Nortriptyline Trimipramine Citalopram Escitalopram Fluoxetine Paroxetine Sertraline Duloxetine Mirtazapine Reboxetine Trazodone Venlafaxine Carbamazepine Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Pregabalin Valproate Topiramate Buprenorphine Co-codamol Co-dydramol Dihydrocodeine Fentanyl Morphine Oxycodone Oxycodone with naloxone Tapentadol Tramadol Cannabis sativa extract Flecainide 5-HT₁-receptor agonists Topical capsaicin Topical lidocaine
Outcome(s)	Patient-reported global improvement (on a 7-point scale) Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale) At least 30% and 50% pain reduction (on a 11-NRS scale) Mean change from baseline pain scores (on a 11-NRS scale) Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design	Parallel triple-blinded randomised controlled trial of at least 12 weeks' study period (they should not have enriched enrolment). All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation. Baseline pain scores between arms should be equal and clearly documented. Concomitant medications should not be allowed or should be restricted and maintained at a stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs. Rescue pain medications either not be allowed or, if used, their use should be accurately documented.

4 Factors affecting participation and quality of life

What are the key factors, including additional care and support, that influence participation and quality of life in people with neuropathic pain?

Why this is important

There is evidence suggesting that people with neuropathic pain experience poorer physical and mental health than people with other forms of pain, even when adjusted for pain intensity. The discrepancy between pain intensity and quality of life implies that other, unrecognisable factors are important for people with neuropathic pain and that these factors may influence their daily activities and participation. Further research should be conducted as described in table 4 below.

**Table 4 Factors affecting participation and quality of life**
Criterion	Explanation
Population	Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include: Central neuropathic pain/central pain Complex regional pain syndromes Compression neuropathies/nerve compression syndromes Facial neuralgia HIV-related neuropathy Mixed neuropathic pain Multiple sclerosis Neurogenic pain Neuropathic cancer pain/cancer pain Neuropathic pain Painful diabetic neuropathy/diabetic neuropathy Peripheral nerve injury Peripheral nervous system disease/neuropathies Phantom limb pain Polyneuropathies Post-amputation pain Post-herpetic neuralgia Post-stroke pain Post-treatment/post-surgery/post-operative pain Radiculopathies/radicular pain* Spinal cord diseases Spinal cord injury Trigeminal neuralgia Note: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.
Intervention(s)	Any important factors, including elements of additional care and support that are perceived as important by adults with neuropathic pain to improve their daily participation.
Comparator(s)	Non-applicable.
Outcome(s)	HRQoL (for example, EQ-5D, WHOQoL- BREF) Measurements of participation (for example, the London Handicap Scale) Satisfaction Patient experiences
Study design	Qualitative research or structured/semi-structured survey questionnaire.

What is the impact of drug-related adverse effects on health economics and quality of life in neuropathic pain?

Why this is important

Pharmacological agents for neuropathic pain are associated with various adverse effects. However, there is little evidence about how this affects cost of the quality of life of patients receiving treatment. Further research should be conducted as described in table 5 below.

**Table 5 Impact of drug-related adverse effects on cost effectiveness and quality of life**
Criterion	Explanation
Population	Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include: Central neuropathic pain/central pain Complex regional pain syndromes Compression neuropathies/nerve compression syndromes Facial neuralgia HIV-related neuropathy Mixed neuropathic pain Multiple sclerosis Neurogenic pain Neuropathic cancer pain/cancer pain Neuropathic pain Painful diabetic neuropathy/diabetic neuropathy Peripheral nerve injury Peripheral nervous system disease/neuropathies Phantom limb pain Polyneuropathies Post-amputation pain Post-herpetic neuralgia Post-stroke pain Post-treatment/post-surgery/post-operative pain Radiculopathies/radicular pain* Spinal cord diseases Spinal cord injury Trigeminal neuralgia Note: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.
Intervention(s)	Any pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Comparator(s)	N/A
Outcome(s)	HRQoL (EQ-5D as well as any condition-specific instruments) in people experiencing adverse effects and people experiencing none Resource-use and costs in people experiencing adverse effects and people experiencing none
Study design	Case–control study This research should be performed in a cohort of people receiving a variety of pharmacological treatments for neuropathic pain. Those experiencing adverse effects should be matched with those experiencing none, and their HRQoL and resource-use/costs compared. Matching should be performed using as many modifiers of HRQoL as possible, including age, sex and underlying diagnosis. Analysis of single, named adverse events and also of people experiencing any serious adverse effect (those leading to discontinuation of the medication in question) would be valuable.

6 Potential for dependence associated with pharmacological drugs for neuropathic pain

Is there a potential for dependence associated with pharmacological agents for neuropathic pain?

Why this is important

There has been some suggestion that some pharmacological agents for neuropathic pain are associated with increased potential for misuse. However, there had not been enough high-quality evidence to adequately explore this issue. Further research should be conducted as described in table 6 below.

**Table 6 Potential for dependence associated with pharmacological drugs for neuropathic pain**
Criterion	Explanation
Population	Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include: Central neuropathic pain/central pain Complex regional pain syndromes Compression neuropathies/nerve compression syndromes Facial neuralgia HIV-related neuropathy Mixed neuropathic pain Multiple sclerosis Neurogenic pain Neuropathic cancer pain/cancer pain Neuropathic pain Painful diabetic neuropathy/diabetic neuropathy Peripheral nerve injury Peripheral nervous system disease/neuropathies Phantom limb pain Polyneuropathies Post-amputation pain Post-herpetic neuralgia Post-stroke pain Post-treatment/post-surgery/post-operative pain Radiculopathies/radicular pain Spinal cord diseases Spinal cord injury Trigeminal neuralgia
Intervention(s)	Any pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Comparator(s)	Any other pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Outcome(s)	Drug dependence (including withdrawal symptoms) Drug abuse or drug misuse
Study design	Long-term follow-up from a randomised controlled trial (minimum 6 months) or community-based observational studies. For trials: Intention to observe dependency and misuse should be made in the study protocol and monitored throughout the study period. All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation. Baseline pain scores between arms should be equal and clearly documented. Concomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs. Rescue pain medications should either not be allowed or, if used, their use should be accurately documented.

Neuropathic pain in adults: pharmacological management in non-specialist settings

Guidance